Epigenetics in Teleost Fish - From Molecular Mechanisms To Physiological Phenotypes PDF
Epigenetics in Teleost Fish - From Molecular Mechanisms To Physiological Phenotypes PDF
Epigenetics in Teleost Fish - From Molecular Mechanisms To Physiological Phenotypes PDF
A R T I C L E I N F O A B S T R A C T
Keywords: While the field of epigenetics is increasingly recognized to contribute to the emergence of phenotypes in
Epigenetics mammalian research models across different developmental and generational timescales, the comparative
Histone modification biology of epigenetics in the large and physiologically diverse vertebrate infraclass of teleost fish remains
Chromatin comparatively understudied. The cypriniform zebrafish and the salmoniform rainbow trout and Atlantic salmon
DNA methylation
represent two especially important teleost orders, because they offer the unique possibility to comparatively
microRNA
Genome duplication
investigate the role of epigenetic regulation in 3R and 4R duplicated genomes. In addition to their sequenced
Zebrafish genomes, these teleost species are well-characterized model species for development and physiology, and
Rainbow trout therefore allow for an investigation of the role of epigenetic modifications in the emergence of physiological
Atlantic salmon phenotypes during an organism's lifespan and in subsequent generations. This review aims firstly to describe the
Environment evolution of the repertoire of genes involved in key molecular epigenetic pathways including histone mod-
Comparative physiology ifications, DNA methylation and microRNAs in zebrafish, rainbow trout, and Atlantic salmon, and secondly, to
Aquaculture discuss recent advances in research highlighting a role for molecular epigenetics in shaping physiological
Aquatic toxicology
phenotypes in these and other teleost models. Finally, by discussing themes and current limitations of the
emerging field of teleost epigenetics from both theoretical and technical points of view, we will highlight future
research needs and discuss how epigenetics will not only help address basic research questions in comparative
teleost physiology, but also inform translational research including aquaculture, aquatic toxicology, and human
disease.
1. Epigenetics and teleost research models Waddington (1968) as ‘the branch of biology which studies the causal
interactions between genes and their products which bring the pheno-
In recent years, the field of epigenetics has received increasing at- type into being’. Since the initial focus on development and phenotype,
tention, which has resulted in a series of papers aiming to provide the investigation of epigenetics has increasingly shifted to molecular
historical context for its development (Haig, 2004; Deans and Maggert, mechanisms, which entail factors regulating ‘heritable changes in gene
2015) in an effort to define clear working definitions for this dynamic expression without changes in the DNA sequence’ (Riggs et al., 1996),
research field (Bird, 2007; Berger et al., 2009; Dupont et al., 2009). which we include as a second definition.
Because of the historical utilization of the term epigenetics in different Together, we therefore define epigenetics as the study of factors that
research contexts on the one hand, and the rapid development of mo- heritably regulate the spatio-temporal genome expression that under-
lecular epigenetics on the other, agreement on a synthetic, clear-cut lies the emergence of physiological phenotypes. Under this definition,
definition has proven challenging. While we acknowledge different epigenetic regulation at the molecular level is mediated by three prin-
viewpoints, we will, for the scope of this review, employ an integrative cipal mechanisms, all of which can heritably alter gene expression
working definition of epigenetics, which firstly emphasizes the link without a change in the DNA sequence. Two of these mechanisms,
between genes, their products and the temporal emergence of the histone modifications and DNA methylation, regulate gene expression
phenotype. This directly reflects the initial definition of epigenetics by at the levels of chromatin structure and DNA, while microRNAs
⁎
Corresponding author.
E-mail address: jan.mennigen@uottawa.ca (J.A. Mennigen).
https://doi.org/10.1016/j.cbpb.2018.01.006
Received 3 September 2017; Received in revised form 8 January 2018; Accepted 16 January 2018
Available online 31 January 2018
1096-4959/ © 2018 Elsevier Inc. All rights reserved.
C. Best et al. Comparative Biochemistry and Physiology, Part B 224 (2018) 210–244
Fig. 1. Conceptual framework of the epigenetic regulation in teleost fish. Environmental (exogenous) and endogenous stimuli are integrated by molecular epigenetic mechanisms to
regulate genomic gene expression, which shapes physiological phenotypes at higher levels of biological organization. Such regulation can occur across ontogenesis and result in the
emergence of physiological phenotypes within a teleost's lifespan (context-dependent epigenetics) and be transmitted between generations (germline-dependent epigenetics).
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In addition to both abiotic and biotic naturogenic environmental 2. The molecular epigenetic toolbox in teleost fish
stimuli any organism experiences across intra- and multigenerational
timescales (Fig. 1), recent focus has shifted to ever increasing anthro- 2.1. Histone modifications
pogenic influences. Endocrine disrupting chemicals in particular have
been identified as epigenetic determinants involved in the intra-, inter-, The most important histone modifications can broadly be categor-
and transgenerational emergence of physiological phenotypes in ized by posttranscriptional modification of specific histone amino acid
mammals (Crews and Gore, 2012). Compared to mammalian model residues by reversible acetylation/deacetylation, methylation/de-
systems however, the investigation of epigenetic mechanisms in teleost methylation and phosphorylation/dephosphorylation (Bannister and
fish has received less attention. This is in spite of the fact that com- Kouzarides, 2011). Generally speaking, these modifications affect the
parative studies of epigenetic mechanisms in the large and physiolo- interactions of basic, positively charged histone proteins with nega-
gically diverse infraclass of teleost fish have the potential to provide tively charged DNA, resulting in different chromatin states, exemplified
important insights in the context of genome evolution, as teleost fish by relaxed, accessible heterochromatin and more condensed, closed
have undergone one, or in the case of salmoniform fish, two additional euchromatin. These chromatin states, in turn, are linked to active and
rounds of genome duplication (Volff, 2005; Betancur-R et al., 2013). inactive gene expression by regulating the accessibility of DNA to
Teleost fish also hold, in addition to their value as research models in proteins and long non-coding RNAs involved in transcriptional reg-
comparative physiology, significant importance for translational re- ulation of genes (Allis and Jenuwein, 2016).
search, especially in the growing sector of aquaculture (Naylor et al., Within the major groups of histone modifications, histone acetyla-
2009; Panserat and Kaushik, 2010; Ulloa et al., 2014), aquatic tox- tion dynamics (Fig. 4A) that largely affect the ε-amino group of lysine
icology (Corcoran et al., 2010; Cossins and Crawford, 2005; Overturf (K) residues at the N-terminal of H3 and H4, are mediated by histone
et al., 2015; Williams et al., 2014), and human disease (Lieschke and acetylases (HATs) and histone deacetylases (HDACs), respectively.
Currie, 2007; 10.1242/dmm.012245, 2014). As such, advances in un- HATs are, based on their location in cytosolic and nuclear cellular
derstanding epigenetic determinants of physiological phenotypes in compartments, further classified into two major families termed type-A
teleost fish are anticipated to translate into applications in these areas. and type B. While type B HATs play a role in initial nuclear deposition
For the purpose of this review, we will principally focus on three key of nascent histones, the more diverse type A family is the principal
teleost model species, the cypriniform zebrafish, Danio rerio, and the regulator of chromatin states and transcription, and is hence considered
salmoniform rainbow trout, Oncorhynchus mykiss, and Atlantic salmon, in more detail in this review. Type A HATs are, based on sequence
Salmo salar. We focus on these species firstly because annotated genome homology and conformational structure, which also dictate their site-
sequences are available (Howe et al., 2013; Berthelot et al., 2014; Lien specificity (Hodawadekar and Marmorstein, 2007), further divided into
et al., 2016), secondly because of their evolutionary position encom- GNAT, MYST and CBP/p300 families, examples of which are provided
passing both teleost- (Ts3R) and salmoniform-specific (Ss4R) genome in Fig. 4A. Conversely, the HDAC-mediated reversal of histone K acet-
duplication events (Volff, 2005; Betancur-R et al., 2013), and thirdly ylation are largely non-specific, but HDAC enzymes are, based on se-
because of their wide use as teleost research models in basic com- quence homology, nevertheless divided into classes I-IV (Yang and Seto,
parative physiology research as well as translational research (Ekker 2007).
and Akimenko, 2010; Craig, 2013). Consequently, these species are of Histone methylation dynamics (Fig. 4B) largely, but not exclusively,
particular interest in advancing the field of comparative epigenetics in occur on histone K residue side chains. In contrast to histone acetyla-
teleost fish. Indeed, while fish genomes and their gene expression have tion, histone methylation occurs in gradual steps of mono-, di-, and tri
been and continue to be well-studied (Fig. 3A-B), the study of reg- methylated states, and does not change the overall charge of the AA
ulatory molecular epigenetic mechanisms (Fig. 3C), specifically histone residue (Ng et al., 2009). Histone lysine methylases (HKMTs) are spe-
modifications (Fig. 3D), DNA methylation (Fig. 3E), and miRNAs cific with regard to site and degree of K methylation and N-terminal K
(Fig. 3F), are only beginning to be investigated in teleost fish. In the residues are methylated by enzymes containing a SET-domain
first section of this review, we use available, NCBI-deposited genome (Bannister and Kouzarides, 2011). Similarly, lysine-specific demethy-
sequence datasets (https://www.ncbi.nlm.nih.gov/genome) to com- lases (LSDs) are discriminatory with regard to site and degree of me-
paratively describe the presence and function of genes representative of thylation (Bannister and Kouzarides, 2011).
three major molecular epigenetic pathways of histone modifications, Histone phosphorylation dynamics (Fig. 4C) are regulated by his-
DNA methylation, and miRNAs in zebrafish (ID 50), rainbow trout (ID tone kinases and phosphatases, respectively, which mainly phosphor-
196), Atlantic salmon (ID 369) and the rat, Rattus norvegicus (ID 73). By ylate and dephosphorylate N-terminal histone serine (S) and tyrosine
comparing deposited sequence synteny and predicted amino acid (AA) (Y) residues. Currently, little is known regarding the recruitment and
sequence similarities of these epigenetic regulator-encoding genes and specificity of these enzymes, but highly dynamic histone phosphoryla-
their products, we aim to identify potential differences and particula- tion is considered to influence histone conformation and DNA interac-
rities in teleost molecular epigenetic toolboxes compared to a mam- tion by introducing a negative charge (Bannister and Kouzarides,
malian reference. In the second section of this review, we highlight 2011).
emerging evidence for the involvement of histone modifications, DNA In teleost fish, representative examples of the HAT classes show
methylation, and miRNA in intra-, inter- and transgenerational de- differential retention patterns in zebrafish and salmoniform genomes
termination of physiological phenotypes in teleost fish in response to compared to the rat, indicating that components of histone acetylation
environmental stimuli. Since research in comparative epigenetics in were differentially affected by Ts3R and Ss4R genome duplication
teleost fish is still emerging, we extend our review to include additional events. For example, the GNAT family HAT atf2, which specifically
fish species, in cases where information for our focal teleost species is acetylates K residues at positions 5, 12 and 15 in H2B, and positions 5, 8
limited. In the third and final section, we then aim to synthesize the and 16 in H4 to activate transcription (Kawasaki et al., 2000), is present
reviewed primary literature to identify emerging themes and current in a single locus across all investigated genomes (Fig. 5A). Both MYST
knowledge gaps in the field of teleost epigenetics and to prioritize re- family HAT kat5a (Fig. 5B), which acetylates the K5 residue of H2A and
search needs and critically review available technical approaches to K14 of H3 and K5, K8, K12 and K16 residues of H4 to activate tran-
address them. We conclude by highlighting importance of this basic scription (Kimura and Horikoshi, 1998), and p300/CBP family HAT
research and its implications for translational research. ep300 (Fig. 5C), which acetylates K residues in all four core histones to
activate transcription (Ogryzko et al., 1996), are present as paralogues
in zebrafish, with additional duplication and differential retention of
these paralogues in salmoniformes. Conversely, hdac3, hdac5, hdac11
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Fig. 3. Historical development of numbers of publications by year (retrieved from NCBI PubMed in November 2017) investigating fish genomes (A) and gene expression (B) compared to emerging studies focusing on fish epigenetics (C) and
specifically the principal molecular epigenetic mechanisms involving histones (D), DNA methylation (E) and microRNA (F). In all cases, searches were conducted using the described specific term indicated on the y-axis in conjunction with the term
‘fish’, ‘zebrafish’, ‘rainbow trout’ and ‘Atlantic salmon’.
Comparative Biochemistry and Physiology, Part B 224 (2018) 210–244
C. Best et al. Comparative Biochemistry and Physiology, Part B 224 (2018) 210–244
Fig. 4. Examples of proteins involved in histone modifications, including histone acetylation (A), histone methylation (B) and histone phosphorylation (C), as determined in mammalian
model systems. See text for detailed descriptions.
and sirt1 genes, coding for representative examples of nonspecific S10 residue of H3 (Soloaga et al., 2003). The later modification is
HDAC classes I-IV that mediate transcriptional silencing, are present in equally mediated by Aurkp, which functions to reorganize chromatin
single loci in rat and zebrafish, but are duplicated in salmoniform during mitosis (Hsu et al., 2000). Conversely, the existence of multiple
genomes (Fig. 6A–D), with the exception of hdac11, the only member of paralogues of representative histone phosphatase genes, such as ppp2ca,
the class IV histone deacetylases. ppp2cb, ppp6c, in salmoniformes suggest a diversification of pathways
Similar to the pattern described for genes encoding for histone involved in controlling histone phosphorylation status via depho-
acetylation dynamics, representative HKMTs involved in histone me- sphorylation (Fig. 10A–C).
thylation dynamics are present in zebrafish both as paralogues, as in the
case of kmt5a and suv39h1, (Fig. 7A–B), or as single loci, as in the case
of ezh2 and ehmt2 (Fig. 7C–D). Following Ss4R, these genes are differ- 2.2. DNA methylation
entially retained in salmoniform genomes. Functionally, Kmt5a med-
iates transcriptional silencing by monomethylating the K20 residue of 2.2.1. Maintenance and de novo DNA methylation
H4 (Nishioka et al., 2002), while Suv39h1 exerts the same effect by DNA methylation enzymes act to methylate cytosines which are
catalyzing K9 trimethylation on H3 (Rea et al., 2000). Similarly, Ezh2 mostly, but not exclusively (Ramsahoye et al., 2000), located in the
induces transcriptional silencing via methylation of K27 in H3 (Cao context of genomic CpG dinucleotides. Such DNA methylation can
et al., 2002), while Ehmt2 elicits transcriptional repression effect via K9 subsequently modify gene transcription as, for instance, methylation of
methylation in in H3 and transcriptional silencing via K27 of the same CpG sequences at transcription start sites (TSS) has been associated
histone (Tachibana et al., 2001). Genes coding for representative ex- with long-term silencing (Jones, 2012). However, DNA methylation
amples of LSDs, specifically kdm1a, kdm6a and kdm6b (Fig. 8A–C), occurs in a variety of genomic contexts outside of promoter regions, and
appear to be present in single loci in rat and zebrafish, but are con- potentially different functional roles of these DNA methylation patterns
sistently retained in duplicate loci in salmoniform genomes following in regulating the genome are still being explored (Ambrosi et al., 2017).
Ss4R. Functionally, Kdm1a specifically removes H3K9me1/2, but Thus, based on genomic context, DNA methylation marks may have
cannot attack the K9 in a trimethylated state (Shi et al., 2004). The permissive roles in gene expression, or primarily mediate chromatin
related LSDs Kdm6a and Kdm6b specifically demethylate H3K27 (Jiang integrity.
et al., 2013b). Collectively these enzymes promote transcription by Based on studies using mammalian model organisms, the enzymes
antagonizing repressive methylation marks previously described. catalyzing DNA methylation are termed DNA methyltransferases
In the three investigated teleost genomes, genes involved in path- (DMNTs), and can be divided into DNMT1 and DNMT3 families
ways modulating histone phosphorylation dynamics appear to have (Fig. 11). While DNMT1 is principally associated with maintenance of
been differentially retained in teleost evolution. While representative DNA methylation in replicating cells (Robertson and Jones, 2000), the
examples of histone kinase genes, specifically rps6ka5 and aurkb appear mammalian DNMT3 family is further divided into DNMT3A, DNMT3B
to be present in single loci in rat and zebrafish, duplicates are retained and DNMTL, and is implicated in de novo establishment of methylation
in salmoniform genomes following Ss4R (Fig. 9A–C). Functionally, marks (Cheng, 2014). However, this distinction likely represents an
Rps6ka5 represses transcription via S1 phosphorylation of H2A (Zhang over-simplification, as overlapping molecular functions have been
et al., 2004), while promoting mitosis via the phosphorylation of the identified for DNMT1 and DNMT3 proteins (Kim et al., 2002; Arand
et al., 2012).
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In teleost fish, the evolutionary history of dnmt genes has been de- the salmoniform lineage that includes duplication, differential retention
scribed for zebrafish, where Ts3R has differentially affected dnmt1 and and loss of specific dnmt3b paralogues (Fig. 12C). This is in line with the
dnmt3 loci (Fig. 12). While dnmt1 is found as a single copy in zebrafish observed diversification of this gene family in teleost fish compared to
(Fig. 12A), two paralogues of dnmt3a (Fig. 12B) and four paralogues of mammalian models in general (Goll and Halpern, 2011; Firmino et al.,
dnmt3b (Fig. 12C) exist, the latter of which have been linked to lineage- 2017), raising the question of functional relevance. While the specific
specific gene duplication events (Campos et al., 2012). Overall, zebra- function of each individual dnmt3b paralogue in teleost fish remains
fish contain a single putative maintenance DNA methyltransferase and unclear, their functional study in teleost fish may prove a fruitful area
six putative de novo DNA methyltransferases, which, based on their of investigation. In mammals, DNMT3B plays a crucial role in DNA
identified splice variants (Smith et al., 2005) and developmental ex- methylation in stem cells (Baubec et al., 2015), centromeric regions,
pression profiles (Smith et al., 2011), are thought to correspond to and germline genes (Walton et al., 2014), and the expansion of the
mammalian DNMT1 and DNMT3 families. Functionally, knockdown of dnmt3b family in teleost fish, and salmoniformes in particular, may thus
zebrafish Dnmt1 and Dnmt3 in has revealed distinct non-com- have functional relevance in these processes. A major difference be-
plementary functions in specific tissue development (Rai et al., 2010), tween teleost and mammalian DNA methylation machinery is the ab-
and differences in developmental dnmt3 paralogue expression profiles sence of DNMT3L (Fig. 12D), whose presence is restricted to genomes of
have reinforced the notion of potential subfunctionalization of dnmt3 eutherian mammals. In these animals, DNMT3L is involved in genomic
paralogues in zebrafish (Campos et al., 2012). In salmoniformes, the imprinting in spite of the lack of a C-terminal catalytic domain
current NCBI deposited rainbow trout and Atlantic salmon genomes (Bourc'his et al., 2001; Chédin, 2011). The functional consequence of its
allow for the unequivocal identification of two distinct dnmt1 loci, absence in teleost fish is not known, but it has been speculated that
providing evidence for the retention of an additional gene copy fol- parent-of-origin-specific epigenetic marks, which ensure monoallelic
lowing the salmoniform-specific genome duplication (Fig. 12A). As for maternal or paternal expression, may be a feature restricted to eu-
dnmt3a, Ss4R has resulted in three and four identified paralogues in therian mammals expressing DNMT3L (Chédin, 2011). However, as the
rainbow trout and Atlantic salmon, respectively (Fig. 12B), while question of whether parental imprinting exists in teleost fish remains
dnmt3b paralogues appear to have undergone a complex evolution in debated (Labbé et al., 2016), it is clear that if it does exist, different
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molecular machinery is involved compared to mammals. and Zhang, 2010; Bhutani et al., 2011). Active DNA demethylation in
mammals is largely mediated via 5-methylcytosine (5mC) oxidation
2.2.2. DNA demethylation catalyzed by members of the ten-eleven translocation (TET) methyl-
DNA demethylation can occur either passively through cell division cytosine dioxygenase family, yielding 5-hydroxymethylcytosine
and absence of maintenance DNA methylation, or actively via enzy- (5hmC) and subsequently 5-formyl-cytosine and 5-carboxylcytosine (Xu
matic pathways, which catalyze the removal of DNA methylation (Wu and Wong, 2015; Kamstra et al., 2015b). Of note, 5hmC itself is
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abundant in the brain of mice (Kriaucionis and Heintz, 2009) and (AICDA), as well as the apolipoprotein B mRNA editing enzyme, cata-
zebrafish (Kamstra et al., 2015b), suggesting a possible epigenetic lytic polypeptide protein (APOBEC). The resulting thymine can then be
function of 5hmC beyond being an intermediate of active demethyla- restored to unmethylated cytosine by base excision repair (Nabel et al.,
tion. Methylcytosine oxidation is followed by action of thymine DNA 2012). However, in vitro conversion of 5mC to thymidine occurs at a
glycosylase (TDG), which recognizes the higher oxidation products of substantially lower rate than cytosine to thymidine, and the importance
5mC and initiates base excision repair, ultimately restoring these as of the AICDA/APOBEC pathway in vivo remains controversial (Nabel
unmethylated cytosines (Kohli and Zhang, 2013). Altogether this de- et al., 2012; Xu and Wong, 2015). As research investigating demethy-
methylation process is known as the TET-TDG pathway (Kohli and lation mechanisms is still an emerging area of study, we focused on the
Zhang, 2013). An alternative pathway has been uncovered in mammals two principal pathways (TET-TDG and AICDA/APOBEC-TDG) de-
(Morgan et al., 2004), which involves 5mC conversion to thymine scribed to date (Fig. 13). With regard to the TET pathway, zebrafish,
through deamination by activation induced cytosine deaminase like mammals, encode one copy of tet1-3 in their genome, while
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salmoniformes retain duplicates of all tet genes following Ss4R both pathways in teleost fish in general, evidence from zebrafish thus
(Fig. 14A–C). In the case of tet2, evidence suggests that salmoniform- suggests activity of both the canonical TET-TDG pathway (Almeida
lineage specific duplications of the tet2b gene resulted in an expansion et al., 2012; Ge et al., 2014), as well as the AICDA/APOBEC pathway
leading to a total of 3 tet2 paralogues (Fig. 14B). With regard to the (Rai et al., 2008; Abdouni et al., 2013).
AICDA/APOBEC pathways (Figs. 14D–H), evidence suggests potential
duplication of aicda following Ss4R (Fig. 14D), and differential patterns 2.3. miRNAs
of apobec gene retention between genomes, (Fig. 14E–H). While
Apobec1 and Apobec3 are found in the rat, but are absent from teleost 2.3.1. miRNA biogenesis
genomes, apobec2 and apobec4 are present as paralogues and individual miRNAs are small non-protein-coding RNA molecules, which target
genes, respectively. The functional significance of the expansion of the specific mRNAs through complementary base pair binding in the 3′
apobec2 gene family in teleost fish is currently unknown. The tdg locus, untranslated region (3’UTR) to reduce the stability and translation of
whose gene product catalyzes the final reconversion to cysteine from the target mRNAs (Ha and Kim, 2014). Mature miRNAs are highly
substrates stemming from both TET and AICDA/APOBEC pathways, conserved in most eukaryotes (Hertel and Stadler, 2015), and are
appears to have undergone a lineage specific duplication event, leading characterized in an increasing amount of teleost fish species (reviewed
to the presence of two paralogues in zebrafish and four in salmoni- by Bizuayehu and Babiak, 2014; Mennigen, 2015). As initially de-
formes (Fig. 14I). The AICDA/APOBEC pathway alternatively utilizes monstrated in mammals and invertebrates, teleost microRNAs repress
methyl binding domain protein 4 (MBD4) in the final step to revert target mRNA abundance or translation (Bazzini et al., 2005). Indeed,
methylated cytosine to cytosine (Hashimoto et al., 2012). In the gen- the canonical pathway for miRNA biogenesis (Fig. 15) is highly con-
omes of the rat and the three investigated teleost fish, a single mbd4 served in animals with the exception of early metazoans (Moran et al.,
locus is retained following whole genome duplication genome 2017), and is well characterized (Ha and Kim, 2014). Briefly, tran-
(Fig. 14J). While little is known regarding the demethylation activity of scription of miRNA genes yields primary miRNA (pri-miRNA), which is
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bound and cleaved by the nuclear microprocessor consisting of the which only a single copy has been retained in salmoniform genomes
endonuclease DROSHA (or ribonuclease 3, RN3), and the DiGeorge (Fig. 16A). While salmoniformes are the only identified species to date
syndrome critical region 8 protein (DGCR8). The pre-miRNA is actively which possess paralogues of several canonical miRNA biogenesis genes,
translocated out of the nucleus by exportin-5 (XPO5), then processed in possible functional implications are currently unknown. In light of the
the cytoplasm by the endoribonuclease DICER to yield mature miRNA. fact that individual miRNAs have a high retention rate compared to
In some cases, post-transcriptional modification of mature miRNAs protein coding genes in salmoniform genomes (an average of three loci
yields so-called isomiRs, which differ from the original mature miRNA per miRNA compared to an average of two loci in zebrafish and a single
sequence either by addition or deletion of individual nucleotides at locus in mammals, as described by Berthelot et al., 2014), this may
either the 3′ or 5′ end derived from differential processing during bio- reflect an increased demand for miRNA processing in the regulation of
genesis or posttranscriptional modifications, or by enzymatically edited salmoniform genomes. Conversely, as paralogues, proteins involved in
nucleotides within the miRNA sequence (Morin et al., 2008; Neilsen miRNA biogenesis may have undergone subfunctionalization in sal-
et al., 2012). While minor, these variations may be functionally re- moniformes and thus evolved to differentially regulate gene expression.
levant, especially when they shift the seed sequence of miRNA molecule To provide an initial distinction between these hypotheses for the
(nucleotide position 2–7), which are particularly important in med- purpose of this review, we utilized a two-tiered in silico approach.
iating specific target recognition (Neilsen et al., 2012). The mature Firstly, we reviewed mammalian literature to identify functionally
miRNA duplex is subsequently loaded into the RNA-induced silencing important AA residues (roles in substrate binding, processing, and ac-
complex (RISC), which contains Argonaute protein 2 (AGO2), the tivity) identified through modeling and mutational analysis, and
principal mediator of decay or translational repression of target mapped these identified AA onto specific predicted protein sequences
mRNAs. Knockout studies in both zebrafish (Giraldez et al., 2005) and from the sequenced teleost genomes in an effort to predict possible
the human cell line HCT116 (Kim et al., 2016), show that Dicer/DICER functional differences between salmoniform paralogues. Secondly, we
activity is necessary for miRNA biogenesis via the canonical pathway, utilized a recently developed comparative fish-specific gene expression
while knockout of other components such as XPO5 allows miRNA atlas termed Phylofish (Pasquier et al., 2016) to identify possible dif-
maturation, albeit with changes in the mature miRNA profile (Kim ferential expression of paralogues between tissues. This approach re-
et al., 2016). vealed specific differences in AA critically involved in miRNA binding
Interestingly, zebrafish retain a single gene copy of canonical between salmoniform XPO5 paralogues (Fig. 17A), which are further-
miRNA biogenesis pathway components (Fig. 16A–E), suggesting that more differentially expressed in different rainbow trout tissues
the Ts3R event, which resulted in the retention of many protein-coding (Fig. 17B). While a possible subfunctionalization in this pathway needs
gene paralogues, did not require the retention of duplicates of the experimental validation, this example serves to illustrate the point that
miRNA biogenesis pathway genes. Conversely, salmoniform species, functional differences in the miRNA biogenesis pathway may exist be-
which have undergone an additional Ss4R event, possess paralogues of tween specific teleost species and mammals.
all miRNA biogenesis pathway genes, with the exception of drosha, for
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Fig. 12. Inferred evolutionary fate of genes dnmt1 (A), dnmt3a (B), dnmt3b (C) and Dnmt3l, which represent different DNMTs. Schematics are based on comparative analysis of NCBI
deposited genome sequences (https://www.ncbi.nlm.nih.gov/genome) of rat (ID: 73), zebrafish (ID: 50), rainbow trout (ID: 196) and Atlantic salmon (ID: 369). The teleost-specific
genome duplication (TsS3R) is indicated by the first red line, while salmoniform species underwent an additional, subsequent lineage-specific genome duplication event (Ss4R). Similarity
of paralogues was established based on available synteny and predicted protein sequence information. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
2014; Kim et al., 2015a, 2015b; Gutierrez-Vazquez et al., 2017). This, in pathway, components of the machinery involved in miRNA turnover
turn, destines the modified miRNAs for degradation mediated by gen- have been retained as single copies in the zebrafish genome, while
eral exonucleases, including the 5′-3′ exoribonuclease 2 (XRN2; Miki components involved in aspects of miRNA turnover are either equally
et al., 2014) and DIS3-like 3′-5′ exoribonuclease 2 (DISL3L2; Pirouz retained as single copies or as paralogues following Ss4R in salmoni-
et al., 2016). Conversely 3′ adenylation mediated by the poly-A poly- form fish (Fig. 19A–I). Whether and how differences in the teleost
merase germline development 2 protein (GLD-2), which is evolutiona- toolbox in miRNA biogenesis and turnover machinery contribute to
rily related to the URT4 and URT7 family (Chung et al., 2016), has been specific miRNA and isomiR profiles characterized in zebrafish
linked with stabilization of some miRNAs (Katoh et al., 2009; Gutierrez- (Presslauer et al., 2017), rainbow trout (Juanchich et al., 2016) and
Vazquez et al., 2017). Deadenylation of GLD2 targeted miRNAs through Atlantic salmon (Andreassen et al., 2013), is currently unknown.
the poly(A)-specific ribonuclease (PARN) and CUGBP Elav-like family
member 1 (CUGBP1) reverses the stabilizing effect of polyadenylation
(Katoh et al., 2015). Similar to the canonical miRNA biogenesis
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Fig. 14. Inferred evolutionary fate of genes tet1 (A), tet2 (B), tet3 (C) and aicda (D), Apobec1 (E), apobec2 (F), Apobec3 (G), apobec4 (H), tdg (I) and mbd4 (J) involved in active DNA
demethylation pathways. Schematics are based on comparative analysis of NCBI deposited genome sequences (https://www.ncbi.nlm.nih.gov/genome) of rat (ID: 73), zebrafish (ID: 50),
rainbow trout (ID: 196) and Atlantic salmon (ID: 369). The teleost-specific genome duplication (TsS3R) is indicated by the first red line, while salmoniform species underwent an
additional, subsequent lineage-specific genome duplication event (Ss4R). Similarity of paralogues was established based on available synteny and predicted protein sequence information.
(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
cell regeneration mediated by Kdm1a (Bao et al., 2017). in nucleosomes containing somatic histones and histone variants, which
All in all, there is overwhelming evidence for developmental roles of is in contrast to the situation in mammals, where genetic material is
all major histone modifications (Fig. 4) across the zebrafish life cycle. packaged by protamines (Wu et al., 2011). Given the presence of his-
Very few studies exist with regard to developmental histone marks in tone modifications in teleost sperm, the question of the fate of estab-
salmoniform species, but histone marks have been identified to con- lished marks across generations arises. With regard to genome regula-
tribute to muscle differentiation in adult rainbow trout in vitro, poten- tion, the generational barrier is represented by maternal to zygote
tially by contributing to differential regulation of pax7 paralogues activation (MZA) at the midblastula transition (MBT), at which ma-
(Seiliez et al., 2015). Regardless of the species studied, most studies ternally inherited regulatory transcripts are degraded and give way to
investigating histone dynamics in teleost have focused on teleost on- zygote-dependent genome regulation (Aanes et al., 2011).
togenesis per se, rather than their regulation in response to exogenous In zebrafish, genome-wide and locus-specific dynamic transition of
environmental stimuli. histone marks have been described between gametes and pre- and post
Historically in rainbow trout, and recently in the zebrafish model, MBT (3 hpf; hours post-fertilization) embryos. Specifically, zebrafish
histone marks have also been studied in the context of intergenerational sperm exhibits both complex multivalent chromatin, in which permis-
transfer. In rainbow trout, somatic cell histones have been shown to be sive and non-permissive marks exist in close proximity, as well as
retained in spermatogenesis where they undergo acetylation, as de- monovalent permissive histone marks (H3K4me3 and H3K14ac) at
monstrated for H2B, H3 and H4 (Candido and Dixon, 1971; Candido genome loci (Lee et al., 2014). These marks were associated with early
and Dixon, 1972; Christensen et al., 1984), methylation, as shown for embryonic gene activation before and after MBT, respectively, sug-
H3 and H4 (Honda et al., 1975) and phosphorylation, as identified for gesting a temporal relevance across MZA. A predictive role for per-
H2B, H3 and H4 (Sung and Dixon, 1970). As in rainbow trout missive and/or repressive H3 methylation marks in zebrafish sperm for
(Avramova et al., 1983), DNA material in zebrafish sperm is packaged MBT stage gene expression has also been described by Lindeman et al.
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exocrine pancreas, and retina, while being dispensable for liver and been observed in the zona limitans intrathalamica, midbrain-hindbrain
endocrine pancreas development. This effect was specifically linked to boundary, ciliary marginal zone, pharyngeal arches, auditory capsule,
Dnmt1-mediated DNA methylation, as only introduction of catalytically pectoral fin buds, intestine, pancreas, liver, and hematopoietic cells in
active Dnmt, but not catalytically inactive Dnmt could rescue the the aorta-gonad-mesonephros and in the caudal tissue from 48 to 72 h
phenotype observed in dnmt1 knockouts (Rai et al., 2006). Conversely, post-fertilization. The expression and function of the additional teleost
dnmt1 mutants reveal time-dependent defects in liver and pancreas lineage-specific dnmt3b paralogues (Fig. 12) remain largely un-
organogenesis, but only after 84 hpf (Anderson et al., 2009). Interest- characterized. In addition to DNMTs, the role of demethylation has
ingly, the pancreatic effects are specific to acinar cells and spare en- equally been addressed in zebrafish, specifically by using tet knockout
docrine cells. Knockout of dnmt1 as well as Dnmt inhibition has fur- lineages. For example, concurrent loss of function of tet paralogues
thermore been shown to regulate zebrafish hematopoiesis (Deveau (Fig. 14) either through morpholino-based approaches (Bogdanović
et al., 2015) and lens development (Tittle et al., 2011). Overall, com- et al., 2016) or knockout approaches (Li et al., 2015) results in major
pared to the relatively detailed functional investigation of maintenance developmental defects in embryos surviving to gastrulation stage which
DNA methyltransferase, the developmental roles of de novo methyl- include short and blended axes, impaired head structures, small eyes,
transferases have largely been explored indirectly by profiling dnmt and reduced pigmentation. In zebrafish tet2−/− and tet3−/− mutants,
paralogue expression in different tissues using in situ hybridization retinal neurons, while specified, fail to terminally differentiate as evi-
(Takayama et al., 2014). This approach suggested potentially over- denced by a lack of axon formation in retinal ganglion cells (Seritrakul
lapping roles for dnmt3aa and dnmt3ab in developmental processes of and Gross, 2017).
the brain, pharyngeal arches, pectoral fin buds, intestine and swim In adult zebrafish, there is evidence for a role for DNA methylation
bladder, while only dnmt3aa was expressed in the developing pro- in tissue regeneration, which may be mediated through both DNA
nephric duct. Conversely, developmental expression of dnmt3b1 has methylation and demethylation pathways. For example, fin
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regeneration following amputation has been linked to strong dnmt3aa reporting no changes in methylation on the one hand (Macleod et al.,
and faint dnmt3ab and dnmt4 expression in blastema cells at 72 h post- 1999), and demethylation and remethylation events on the other
amputation (Takayama et al., 2014). Zebrafish dnmt1 mutants and (Mhanni and McGowan, 2004). This difference was attributed to an
morpholino-injected larvae revealed increased beta cell regeneration earlier demethylation window in zebrafish development compared to
capacity (Anderson et al., 2009). Inhibition of Tet activity that pre- mammals (Mhanni and McGowan, 2004), a finding recently confirmed
vented demethylation and generation of Tet-induced cytosine inter- by higher-resolution methylation measurements using whole-genome
mediates reestablished the capacity for tissue regeneration in a hy- shotgun bisulphite sequencing (Jiang et al., 2013a; Potok et al., 2013).
perglycemic zebrafish model for diabetes (Dhliwayo et al., 2014). Of note, both recent studies uncovered not only a temporal difference in
Finally, retinal injury in zebrafish stimulates Müller glia to undergo a DNA methylation dynamics after fertilization between zebrafish and
reprogramming event that transitions their identity from quiescent mammals, but also a qualitative difference. In zebrafish, the restored
supportive cells to multipotent progenitors capable of repairing the methylation pattern in zygotes at the MBT closely matches the sperm
damaged retina, which is associated with a changing DNA methylation genome methylation pattern, which is hypermethylated compared to
landscape (Powell et al., 2013). the hypomethylated oocyte. Thus, the maternally inherited genome
The most crucial differences in DNA methylation dynamics between undergoes DNA methylation changes to match the paternal methylation
teleost fish, or at least zebrafish and mammalian model systems have pattern at MBT, and the paternally inherited methylation pattern pro-
been uncovered in an intergenerational context. Initial investigation of vides a ‘blueprint’ for early embryogenesis following MBT. Following
temporal DNA methylation dynamics from zebrafish sperm to zygotes MBT, increased DNA methylation in CpG sites and LINEs, as well as
at different post-fertilization timepoints provided conflicting results, decreased DNA methylation in SINEs finally lead to a clear
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study of specific epigenetic marks in these cells in the future. The study
of DNA methylation dynamics in teleost PGCs may also provide im-
portant insight into their differential role in sex determination between
zebrafish (Slanchev et al., 2005) and Atlantic salmon (Wargelius et al.,
2016).
Finally, at the evolutionary scale, emerging evidence suggests a role
for DNA methylation in the regulation of paralogues in duplicated tel-
eost fish genomes (Zhong et al., 2016), confirming reports of a role for
differential methylation in duplicated genes in humans (Keller and Yi,
2014). Such epigenetic regulation of duplicated teleost genomes may
contribute to the widespread success of teleost fish in occupying diverse
ecological niches with a wide range of environmental conditions (Volff,
2005), and future comparative studies involving additional teleost fish
species are warranted.
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Fig. 19. Inferred evolutionary fate of genes tut4 (A), tut7 (B), gld2 (C) bcdin3d (D), cugbp1 (E), henmt1 (F) xrn2 (G), dis3l2 (H) and parn (I), involved in miRNA turnover pathways, as
determined in mammalian models. Schematics are based on comparative analysis of NCBI deposited genome sequences (https://www.ncbi.nlm.nih.gov/genome) of rat (ID: 73), zebrafish
(ID: 50), rainbow trout (ID: 196) and Atlantic salmon (ID: 369). The teleost-specific genome duplication (TsS3R) is indicated by the first red line, while salmoniform species underwent an
additional, subsequent lineage-specific genome duplication event (Ss4R). Similarity of paralogues was established based on available synteny and predicted protein sequence information.
(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
and pancreas-enriched miRNA-375, which have all been shown to play regulator of MZA by promoting clearance of maternally-deposited germ
a role in tissue differentiation and/or homeostasis in both zebrafish plasm RNAs in somatic but not germ cells (Mishima et al., 2006).
(Kloosterman et al., 2007; Mishima et al., 2009; Laudadio et al., 2012)
and rainbow trout (Mennigen et al., 2013; Mennigen et al., 2014a;
Latimer et al., 2017). 4. A role for (molecular) epigenetics in teleost environmental
While inter- and possibly transgenerational roles for miRNAs physiology
transmitted as parental cargo in sperm or eggs are emerging as de-
terminants of physiological phenotypes in mammals (Rodgers et al., Following the description of specific characteristics of the teleost
2015; Smythies et al., 2014; Vilella et al., 2015), their comparative role epigenetic toolbox, the spatiotemporal dynamics of epigenetic marks
in teleost fish remains unknown. This is in spite of the fact that miRNAs and their mechanistic function in teleost model species, we here address
have been quantified in zebrafish sperm and eggs (Jia et al., 2015; the increasing evidence for environmental and/or endogenous regula-
Presslauer et al., 2017) and in rainbow trout eggs (Ma et al., 2012; Ma tion of these epigenetic marks. Specifically, we highlight how molecular
et al., 2015), underlining the feasibility of investigating potential inter- epigenetic marks in zebrafish and salmoniform species are altered in
and/or transgenerational roles for miRNAs in teleost fish. A notable response to diverse naturogenic and anthropogenic environmental
exception to the general lack of knowledge concerning miRNAs as conditions relevant to aquatic species in intra-, inter- and transge-
possible mediators of inter- or transgenerational inheritance is the well- nerational settings (Fig. 1). Where possible, we aim to describe how this
established role of miRNA-430, which has been identified as a key (molecular) epigenetic regulation in response to environmental stimuli
integrates into physiological phenotypes. In cases where studies in
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zebrafish, rainbow trout and Atlantic salmon are currently limited, we Varriale, 2014). In more recent studies, temperature-dependent DNA
include additional teleost species in an attempt to synthesize current methylation dynamics have been addressed in muscle tissue of zebra-
information in teleost models. fish (Campos et al., 2012; Han et al., 2016), Atlantic salmon
(Burgerhout et al., 2017) and Senegalese sole, Solea senegalensis,
4.1. Hypoxia (Campos et al., 2013). In zebrafish, dnmt paralogues were found to be
differentially regulated in response to rearing temperature, with higher
Teleost fish evolved to inhabit diverse niches with varying degrees temperatures favouring an increase in dnmt3a and concomitant de-
of oxygen availability (Rogers et al., 2016). While histone-dependent crease in dnmt3b, suggesting changes in DNA methylation (Campos
chromatin modifications are involved in the hypoxia response in et al., 2012). In zebrafish fibroblast cells (ZF4) exposed to a low tem-
mammalian models (Melvin and Rocha, 2012; Hancock et al., 2015), perature of 18 °C compared to the standard conditions of 28 °C, MeDIP
the role of histone modifications in context-dependent epigenetic reg- sequencing revealed changes in global DNA methylation patterns
ulation of the genome in teleost fish experiencing hypoxia remains characterized by an increase after 5 d and a decrease after 30 d. Overall
unexplored. Using ChIP-assay/DNA-seq and forced expression ap- 21% of DNA methylation peaks were differentially affected by these
proaches in zebrafish, detailed, genome-wide maps of hypoxia-re- temperature treatment regimes, of which the majority (92%) did not
sponsive elements and hypoxia regulated transcripts have become affect promoter regions. Functionally, differentially methylated gene
available (Zhang et al., 2014b; Greenald et al., 2015), which will loci were enriched for functions in folate metabolism, the antioxidant
greatly facilitate future targeted studies investigating histone-depen- system, the immune system, apoptosis and chromatin modification,
dent regulation of hypoxia responsive genes in zebrafish. While hypoxic suggesting DNA methylation, possibly in crosstalk with histone mod-
stimuli have been investigated across development in rainbow trout to ifications, plays a role in regulating these pathways involved in cold-
investigate consequences on metabolic gene expression (Liu et al., acclimation (Han et al., 2016). In Atlantic salmon, embryos selected for
2017a; Liu et al., 2017b), a potential role for histone modifications in fast and slow growth were incubated at 4 °C and 8 °C prior to seawater
the regulation of these genes has not been investigated. In an inter- and transfer, and in the fast-growth group incubated at the warmer tem-
transgenerational context, F0 hypoxia exposure has been linked to in- perature, growth performance was correlated with increased larval
creased hypoxia tolerance tolerance in F1 zebrafish (Ho and Burggren, myogenin expression, which in turn exhibited low DNA methylation
2012), and reproductive impairment in F1 and F2 male marine medaka, levels. This study suggests environment and genome differentially affect
Oryzias melastigma (Wang et al., 2016b). Mechanistically, the hypoxia- epigenetic regulation of myogenin in Atlantic salmon (Burgerhout
induced phenoype in marine medaka, was linked to increased expres- et al., 2017). In Senegalese sole, Solea senegalensis, specific analysis of
sion of the euchromatic histone-lysine N-methyltransferase 2 (ehmt2) in gene promoters using bisulfite sequencing revealed the occurrence of
the testes across generations, which, in turn, was linked to hypo- hypermethylated myogenin (myog) promoters coinciding with lower
methylation of its promoter. The increase in ehmt2 was linked to an growth rates in fish reared at colder temperatures (Campos et al.,
increase in cells positive for its catalyzed histone mark H3K9me2, 2013). An interesting additional context-dependent effect of epigenetic
suggesting a concerted role for DNA methylation and histone mod- mechanisms in response to temperature but unrelated to the physiology
ifications in this phenotype (Wang et al., 2016b). of growth and metabolism has been discovered in seabass, Dicentrarchus
Several studies have investigated hypoxia-induced regulation of labrax, a species in which sex is determined by both genetics and
miRNA abundance. A hypoxia-inducible factor 1 (hif1)-dependent in- temperature (Navarro-Martín et al., 2011). In seabass, temperature-
crease in miRNA-462/731 has been described in zebrafish larvae under dependent methylation of the cyp19a (aromatase) promoter region is an
hypoxic conditions, and miRNA-462/731 was shown to target the genes important mediator of sex determination (Navarro-Martín et al., 2011),
deadbox helicase 5 (ddx5) and Mg2+/Mn2+ dependent protein phos- a mechanism that has subsequently been validated in other fish species
phatase (ppm1da) to regulate cell survival (Huang et al., 2015). More and non-teleost species exhibiting temperature-dependent sex de-
evidence stems from additional studies in the beloniform marine me- termination (Wang et al., 2017b; Matsumoto et al., 2013). Potential
daka, for which differential expression of miRNAs in several tissues in germline-dependent epigenetic changes in response to temperature in
response to hypoxia has been described (Lau et al., 2014). Specific in- teleost fish have not yet been fully addressed, although Shao et al.
vestigation of these differentially expressed miRNAs under hypoxia (2014) recently demonstrated transmission of temperature effects on
have pointed to anti-apoptotic and steroidogenic target genes in the sex determination in half-smooth tongue sole, Cynoglossus semilaevis, in
same species, highlighting their role in mediating cell survival on the that some ZW females in the offspring of heat-exposed fish developed as
one hand, but also reproductive impairment observed under hypoxia on males, even in the absence of elevated temperatures.
the other (Lai et al., 2016; Tse et al., 2015; Tse et al., 2016). Context-dependent regulation of miRNAs in response to develop-
mental or acute changes in water temperature has been relatively
4.2. Temperature widely studied, largely using the zebrafish model (Hung et al., 2016;
Johnston et al., 2009; Yang et al., 2011) and several commercially
To our knowledge, no studies have comparatively investigated important aquaculture species, including Senegalese sole (Campos
global histone modifications and chromatin states in stenotherm fish et al., 2014) and Atlantic cod, Gadus morhua (Bizuayehu et al., 2015). In
species. However, a few studies have investigated the involvement of most cases, muscle tissue was targeted for analysis, and transcriptomic
histone marks in temperature acclimation in eurytherm fish. For ex- screening approaches identified numerous differentially regulated
ample, liver cells of winter-acclimated (8–10 °C) common carp, Cyprinus miRNAs between groups developing in different temperature regimes.
carpio, exhibited increased abundance of the heterochromatin marks Some of these temperature regulated miRNAs include deeply conserved
H3K4me3 and of the histone variant macroH2a compared to summer and muscle-specific miRNAs termed myomiRs such as miRNA-1/133
acclimated (20–22 °C) cells. These increased histone marks in cold- and miRNA-206, which have previously been shown to coordinate
adapted carp liver cells correlated with hypermethylated CpG sites in ontogenic muscle development in zebrafish (Mishima et al., 2009) and
the promoter region of ribosomal protein genes, whose expression was Nile tilapia, Oreochromis niloticus (Yan et al., 2013). Together, these
significantly decreased in the winter (Pinto et al., 2005). findings suggest that miRNA control of muscle development can be
With regard to temperature effects on teleost DNA methylation, modulated by temperature. Nevertheless, other than through standard
comparative, ecological-level studies identified global methylation practice in silico target prediction (Brennecke et al., 2005), the func-
differences across a vast array of teleost fish species as a function of tional relevance of these temperature-dependent miRNA changes was
habitat water temperature, with hypermethylated DNA in cold-water not probed experimentally. Furthermore, it becomes apparent that a
species compared to warm-water species (Varriale and Bernardi, 2006; large number of miRNAs regulate temperature-driven processes in a
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tissue- and species-specific manner, and further investigation is war- 4.4. Nutrition
ranted to understand conserved miRNA-mRNA relationships in re-
sponse to temperature changes at multiple timepoints. Teleost fish exhibit a wide diversity of feeding strategies, and are
represented on practically every trophic level, from herbivores to ter-
4.3. Salinity and pH tiary predators to decomposers (Gerking, 1994; Braga et al., 2012). As
nutrition is of particular interest to aquaculture (Naylor et al., 2009), it
In their diverse aquatic habitats, fish have evolved varied strategies is not surprising that most studies investigating nutritional epigenetic
to maintain osmotic homeostasis in environments with different and/or regulation in teleost fish stem from a variety of aquacultured species
fluctuating salinity and pH (Greenwell et al., 2003). Recent evidence (Panserat and Kaushik, 2010) in addition to zebrafish (Ulloa et al.,
revealed that osmotic challenges result in context-dependent changes in 2014). Context-dependent nutritional regulation of histone modifica-
histone modifications, DNA methylation and miRNA abundance in tions has been described in zebrafish, rainbow trout and blunt snout
several tissues crucially involved in osmoregulation in cypriniformes, bream. In muscle of zebrafish, which had been re-fed after a 7 d star-
especially gill and kidney. In the gill tissue of the euryhaline teleost vation period, the expression of the histone modifying enzymes, smyd1b
Gillichtys mirabilis, hypoosmotic stress led to an acute and significant and ehmt1b was induced 5-fold, suggesting a role for histone mod-
decrease in phosphorylated H3 protein abundance, a marker of cell ifications in acute nutritional regulation of the muscle transcriptome
division, while histone H2b was induced at the gene expression level (Amaral and Johnston, 2011). Zebrafish myogenic precursor cells
(Evans and Somero, 2008). Conversely, the mRNA abundance of the starved in a medium devoid of serum and amino acids were shown to
histone H1 family member was downregulated under hyperosmotic induce the expression of several autophagy related genes, which coin-
stress (Evans and Somero, 2008). Together, these data show that his- cided with differential changes of H3K27me3, H3K9me3, and
tone-dependent modification is involved in gill tissue plasticity in re- H3K4me3 histone modifications in the promoter region (Biga et al.,
sponse to context-dependent osmotic challenges. 2017). In carnivorous and glucose-intolerant rainbow trout, acute
Global DNA methylation changes detected by methylation-sensitive feeding of a carbohydrate-rich diet resulted in hyperglycemia as well as
amplified polymorphism (MSAP) were identified between gills of global and promoter specific changes of histone marks in the liver
freshwater- and seawater-reared brown trout, Salmo trutta (Morán et al., (Marandel et al., 2016). Specifically, permissive H3K9ac histone marks
2013). Similarly, in the same study, DNA methylation changes were were globally increased in rainbow trout re-fed with a protein-rich diet,
also observed following the administration of a salt-enriched diet in while H3K36me3 marks displayed greater enrichment around the TSS
freshwater reared brown trout, albeit in the short term only (Morán of specific gluconeogenic gene loci of trout fed a protein-rich diet
et al., 2013). Gene specific DNA methylation changes have been de- compared to trout fed a carbohydrate-rich diet. Equally in rainbow
scribed in the half smooth tongue sole, Cynoglossus semilaevis, in re- trout, early life vitamin intake resulted in global H3 acetylation, H3K4
sponse to salinity exposure of 0.15% (Li et al., 2017). Specifically, this methylation and changes in hepatic DNA methylation (Panserat et al.,
exposure resulted in retarded growth and was associated with high liver 2017). This is the first evidence to suggest that short-term vitamin
insulin growth factor (igf) gene methylation and conversely decreased stimulus during early life results in gene expression changes driven, at
igf mRNA abundance level (Li et al., 2017). No germline-dependent least in part, by methylation and acetylation of histones. In the seabass,
effects of osmotic challenges and underlying DNA methylation patterns Dicentrarchus labrax, plant diet supplementation with sodium butyrate,
have been investigated in teleost fishes to date. a fermentation by-product, for a period of 8 weeks increased the acet-
A series of studies in Nile tilapia showed that osmotic stimuli reg- ylation level of hepatic H4K8 twofold, while increasing ehmt2 and
ulate gill and kidney miRNAs and are functionally involved in med- hdac11 mRNA abundance in liver (Terova et al., 2016). This coincided
iating molecular and organismal level responses to maintain home- with regulation of cytokine-encoding transcripts, however whether
ostasis when exposed to osmotic stress (Yan et al., 2012a, 2012b; Zhao both phenomena are linked was not addressed in the study.
et al., 2016a). In gill tissue, osmotic stress decreases miRNA-429 ex- Nutritional context-dependent changes in DNA methylation have
pression, which in turn has been shown to upregulate osmotic stress been reported in both cypriniformes and salmoniformes. In a zebrafish
transcription factor 1 (Ostf1) protein abundance (Yan et al., 2012b). In model of diabetes, hyperglycemia results in context-dependent genome-
kidney tissue, miRNA-30c inhibition leads to a loss of osmotic stress wide hypomethylation of specific CpG sites, which have been shown to
tolerance, which, at least in part, may be related to its ability to regulate be mitotically transmissible to previously unexposed daughter cells
Hsp70 protein abundance in vivo (Yan et al., 2012a). In tissue and cells during tissue regeneration, providing evidence for their involvement in
of Nile tilapia, miR-21 is inhibited under alkaline stress, leading to metabolic memory in impaired wound healing (Olsen et al., 2012). In
induction of potentially protective vascular endothelial growth factors response to diet-induced hyperglycemia, global and specific DNA me-
vegfb and vegfc at the mRNA level (Zhao et al., 2016a). In zebrafish, thylation changes have been observed in the liver of rainbow trout
studies examining ionocytes in embryos identified members of the (Marandel et al., 2016). Specifically, rainbow trout fed a carbohydrate-
miRNA-8 family to bind to the Na+/H+ exchanger regulatory factor 1 rich diet exhibited global hypomethylation of hepatic DNA compared to
(nherf1), and knockdown of miRNA-8 family members caused increased trout fed a protein-rich diet, while hypomethylation of CpG sites in
rates of edema, suggesting a functional role of this pathway in ionocyte- putative promoter sequences of specific g6pc2 paralogues (glucose-6-
dependent osmoregulation (Flynt et al., 2009). In Atlantic salmon, phosphatase) correlated with their paradoxical induction in response to
context-dependent changes in miRNA have been observed: an acidic a high carbohydrate diet (Marandel et al., 2016). Dietary restriction of
challenge altered the muscle miRNA profile, although these fish were methionine, a nutritional precursor for the DNA methylation process,
co-exposed to 80 μg/L aluminum, so the effect of the acidic challenge resulted in a phenotype of improved glucose tolerance in the same
alone is unclear (Kure et al., 2013). In three-spined stickleback, Gas- species but did not coincide with global DNA methylation changes in
terosteus aculeatus, a model organism to study the molecular mechan- the liver. The liver did however exhibit a tendency for hypomethylation
isms of freshwater adaptation and speciation, a comparative study of in response to a carbohydrate rich diet in the same study (Craig and
gill tissue of marine and freshwater populations revealed that a total of Moon, 2013), and analysis of promoter and/or gene-specific DNA me-
10 miRNA genes were localized in so called genomic ‘divergence is- thylation changes may provide a more informative link between DNA
lands’, which are characterized by a high content of SNPs, suggesting a methylation and physiological phenotype.
possible role for differential regulation of these miRNAs in the evolu- Context-dependent nutritional regulation of miRNAs has equally
tion of freshwater tolerance (Rastorguev et al., 2016). To date no inter- been studied in zebrafish and aquaculture species, largely focusing on
or transgenerational studies on osmoregulation have been conducted in nutritional regulation of key metabolic pathways related to macro-
teleost fish. nutrient utilization and tissue differentiation (Mennigen, 2015). In
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zebrafish, a microarray was used to determine changes in hepatic are aberrantly expressed under ethanol exposure, persistently pheno-
miRNA and 9 differentially expressed miRNAs were identified, among copy the effect of ethanol to increase swimming, an effect linked to
which let7-d and miR-140-5p were inversely correlated to predicted changes in brain morphogenesis and craniofacial development (Tal
target mRNA abundance of the α1 and α2 subunits of the metabolic et al., 2012). Whether miRNAs in teleost fish can, in addition to their
sensor adenosine monophosphate-activated protein kinase ampk (Craig developmental effects, act as direct mediators of rapid behavioural
et al., 2014). In rainbow trout liver, postprandial induction of the plasticity as described for histone modifications and DNA methylation
highly abundant and liver-specific miRNA-122 (Mennigen et al., 2012) is currently unknown. However, recent findings in the fruitfly, Droso-
was shown to be dependent on insulin and/or macronutrient compo- phila melanogaster, indicate that miRNAs are capable of mediating rapid
sition (Mennigen et al., 2014b), and to be functionally involved in the behavioural responses (Picao-Osorio et al., 2015; Picao-Osorio et al.,
regulation of postprandial glucose and triglyceride homeostasis, likely 2017) and an involvement of miRNAs in diverse acute behavioural
by regulating fatty acid synthase protein abundance (Mennigen et al., responses in teleost fish will provide for an interesting avenue of future
2014a). In other aquaculture species, macronutrients have also been investigation.
shown to affect the miRNAs in key metabolic tissues. Studies in the The involvement of molecular epigenetic mechanisms in possible
glucose-tolerant blunt snout bream, Megalobrama amblycephala, showed inter- and transgenerational transmission of social interaction on teleost
that a high starch diet differentially regulated miRNAs in intestine, fish behaviour have not yet been widely investigated in fish, in spite of
liver, and brain using next generation sequencing, which were pre- its direct consequences on organismal fitness. In three-spined stickle-
dicted to target genes in insulin signaling, and carbohydrate and lipid backs, paternal care reduces indices of offspring anxiety, a trait con-
metabolic pathways (Miao et al., 2017). In the same species, a high sidered to render offspring more vulnerable to predators (McGhee and
lipid diet equally affected the miRNA profile in the liver and was pre- Bell, 2014). Importantly, reduced anxiety in offspring exposed to pa-
dicted to target key genes in lipid metabolism, including fatty acid ternal care co-related with brain expression of the de novo DNA me-
synthase and NADH dehydrogenase (Zhang et al., 2014a). thyltransferase dnmt3 (McGhee and Bell, 2014), suggesting a context-
Possible intergenerational effects of nutritional programming are dependent inter-generational epigenetic effect that is mediated by DNA
beginning to be explored in aquaculture species, for example in methylation.
rainbow trout adapted to plant-based diets (Lazzarotto et al., 2015;
Lazzarotto et al., 2016), however the possible involvement of epigenetic 4.6. Pathogens
mechanisms in identified transcriptomic changes was not explored in
these studies. The environmental regulation of the teleost immune system is
widely studied to investigate innate and adaptive immune responses in
4.5. Conspecific and heterospecific social interaction a basal vertebrate, and to limit disease outbreaks in aquaculture set-
tings (Levraud and Boudinot, 2009; Rubio-Godoy, 2010). Similar to
Among the studies investigating environmental regulation of epi- other environmental factors, pathogens have been shown to cause
genetic marks in teleost fish, recent evidence suggests involvement of histone modifications, DNA methylation changes and alteration of
epigenetic mechanisms in response to social interaction in several tel- miRNA abundance in teleost immune tissues. For example, microbial
eost fish species. For example, a role for histone modifications in re- priming in zebrafish is facilitated by chromatin modifications in the
sponse to short, intense interaction with conspecifics comes from a form of H3K9ac and H3K4me3 marks in promoter regions of the cy-
recent study of territorial male three-spined sticklebacks, which were tokine-encoding genes il1β, il12α, and tnfα following treatments with
exposed to a brief territorial challenge (Bukhari et al., 2017). In the either trichostatin A, or pargyline, which act to inhibit histone deace-
brain of challenged males, H3K27ac, a marker of chromatin accessi- tylase and LSD1, a H3K4 demethylase. These histone modifications
bility, changed dynamically and rapidly at several genome loci, as result in an increased expression of these cytokines in response to DNA
evidenced by 30- to 40-fold changes for individual peaks as early as 0.5 from the pathogen Vibrio anguillarum prior to the development of
and 2 h following the encounter. Differentially expressed genes in- adaptive immunity (Galindo-Villegas et al., 2012). In adult zebrafish
cluded those involved in immune function and long-term potentiation, with developed adaptive immunity, exposure to a chronic disease in-
suggesting roles for brain histone modifications in recovery, and pre- ducing strain (E11) of pathogenic mycobacteria caused significant
paration for future encounters (Bukhari et al., 2017). With regard to downregulation of several histone family members compared to ex-
context-dependent DNA methylation, a recent manipulative study in posure to an acute disease-inducing strain (Mma20). This suggests an
the African cichlid fish, Astatotilapia burtoni, revealed that pharmaco- involvement of histone modifications in response to chronic disease
logically induced global hypomethylation changes significantly de- inducing strains, which may be related to the coincidental regulation of
creased the likelihood of becoming socially dominant when competing genes involved in immune system development (van der Sar et al.,
with a conspecific for 30 min (Lenkov et al., 2015). The treatment ad- 2009). With regard to salmoniformes, histone variants themselves have
ministered to reduce global methylation, which significantly inhibited long been shown to have direct antimicrobial properties, as exemplified
social ascension, was specifically linked to increased methylation of a by histone variants found in Atlantic salmon and rainbow trout
CpG island in the gnrh gene, which is known to be rapidly induced in (Richards et al., 2001; Fernandes et al., 2002). However, the role of
socially ascending males, ostensibly to promote reproductive success epigenetic histone modifications in response to pathogens in salmoni-
(Lenkov et al., 2015). With regard to longer developmental timeframes, form species has not yet been explored.
different early life social experience (in the form of exposure to parents With regard to pathogen-induced context-dependent DNA methy-
and sibling conspecifics compared to siblings alone) in the co- lation changes, a series of studies investigating DNA methylation in
operatively breeding cichlid Neolamprologus pulcher resulted in lower grass carp, Ctenopharyngodon idella, in response to grass-carp reovirus
brain expression of crf (corticotropin releasing factor) and gr1 (gluco- (GCRV) identified differential gene-specific (Shang et al., 2015; Shang
corticoid receptor 1; both involved in hypothalamic–pituitar- et al., 2016) and genome-wide DNA methylation patterns (Shang et al.,
y–interrenal (HPI) axis regulation) 1.5 years after the social stimulus 2017). Specifically, hypermethylation of individual CpG sites in the
(Taborsky et al., 2012), suggesting programming via molecular epige- flanking and coding regions of rig1 and mda5 was found to be inversely
netic mechanisms. However, specific epigenetic mechanisms were not correlated the encoded mRNA abundance in the spleen and associated
investigated in this study. Evidence for a role of miRNAs in teleost with increased disease susceptibility.
behaviour includes a study in juvenile zebrafish, which develop hy- Compared to histone modification and DNA methylation, miRNAs
peractivity following developmental exposure to ethanol (Tal et al., have been heavily studied in tissues important in mounting immune
2012). Specifically, the knockdown of miRNA-9 or miRNA-153, which responses to viral and bacterial exposures in many teleost fish, and this
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field of research has also been advanced by studying many aquaculture compared transcriptomic responses to a wild population may serve as
species of economic interest. In some teleost species, miRNAs have been cautionary example, as laboratory housing, rather than contaminants,
shown to contribute to host defense by directly targeting viral tran- identified an enrichment of histone modification in the transcriptome
scripts. In a greasy grouper spleen cell line (Epinephelus tauvina), and a (Baillon et al., 2016). This study therefore underlines that care must be
fathead minnow epithelial cell line (Pimephales promelas), miR-13 was applied when extrapolating contaminant induced epigenetic regulation
induced in Singapore grouper iridovirus (SGIV)-infected cells and tar- between wild and laboratory raised animals.
geted viral SGIV-MCP (major capsid protein) mRNA, resulting in The plasticizer and endocrine disrupting chemical Bisphenol A
blockade of MCP translation, and attenuation of viral assembly (Yan (BPA) has recently also been shown to modulate histone marks in
et al., 2015). In SSN1 cells of the snakehead, Channa striata, infection ovaries of sexually mature zebrafish, which had been exposed to BPA
with snakehead vesiculovirus (SHVV) resulted in down-regulation of concentrations consistent with environmental exposures for a period of
miRNA-214, which interferes with viral replication by targeting N and three weeks (Santangeli et al., 2016). Specifically, BPA exposure de-
P proteins, suggesting co-evolution of miRNA and pathogen (Zhang creased the permissive H3K4me3 mark and conversely caused an en-
et al., 2017c). Conversely, in common carp, CyHV3 encoded miRNA richment of the silencing H3K27me3 mark in the transcription start site
MR5057-mir-3p directly regulates gene expression of a CyHV3 encoded (TSS) of the star and fshr genes, which play roles in steroidogenesis,
dUTPase, while the regulation of possible host targets was not in- oocyte growth, and oocyte maturation (Santangeli et al., 2016). Since
vestigated in this study (Donohoe et al., 2015). In a detailed review these changes coincided with a BPA induced atresia, zona radiata
investigating the regulation of host cell miRNAs by viral and bacterial breakdown, and yolk resorption at the tissue level and complete im-
infections in teleost fish, Andreassen and Høyheim (2017) identified pairment of fertility after 8 days of treatment at the organismal level,
distinct (and often teleost-specific) miRNA expression patterns in re- this study implies that underlying histone modifications play a role in
sponse to viral infection, bacterial infection, or both, which were pos- BPA-induced reproductive disruption in female zebrafish. To our
tulated to control the time-dependent activation and inhibition of knowledge, inter- and transgenerational studies of contaminant-in-
specific host immune responses. Pathogen-dependent regulation of duced histone modifications, either in gametes or specific tissues in
epigenetic marker in the germ-line, and possible consequences on subsequent generations have not yet been explored in teleost fish.
transgenerational phenotypes have not been described in teleost fish to DNA methylation changes in response to aquatic contaminants have
date. been more widely studied in teleost fish, and have largely focused on
determining context-dependent changes in expression profiles of dnmt
4.7. Anthropogenic effects on teleost epigenetics paralogues, Dnmt activity and differential global or specific DNA me-
thylation, the latter of which have been assessed both genome-wide and
In addition to environmental conditions discussed above, anthro- in promoter regions of specific genes. These studies have almost ex-
pogenic activity can influence teleost physiology indirectly, through the clusively been conducted in the zebrafish model, testifying to this
modification of naturogenic environmental factors discussed above, or emerging model's promise to further our understanding of the effects of
directly in the form of aquatic contaminants. Examples of indirect an- contaminant exposure on mechanisms regulating DNA methylation
thropogenic factors affecting teleost physiology are, for example, hy- dynamics (Kamstra et al., 2015a; Bouwmeester et al., 2016). As such,
poxic dead zones (Diaz and Rosenberg, 2008; Wang et al., 2016b), changes in zebrafish DNA methylation indices have been reported in
global warming (Wood and McDonald, 1997; Comte and Olden, 2017), response to a wide-range of aquatic contaminants, including metals
ocean salinity changes (Ojaveer and Kalejs, 2005; Helm et al., 2010), (Gombeau et al., 2016; Zheng et al., 2017; Sanchez et al., 2017; Carvan
ocean acidification (Doney et al., 2009; Welch et al., 2014) and algal- et al., 2017), industrial products (Laing et al., 2016; Liu et al., 2016b;
bloom derived microcystins (Liu et al., 2014; Brzuzan et al., 2016). As Santangeli et al., 2016; Zhao et al., 2017b), pesticides (Wirbisky-
previously described, these environmental factors can elicit molecular Hershberger et al., 2017; Qian et al., 2017), persistent organic pollu-
epigenetic changes in teleost fish, which contribute to shaping phy- tants (POPs; Aluru et al., 2015), and polycyclic aromatic hydrocarbons
siological responses across different timescales. In additional instances, (PAHs; Gao et al., 2017; Kuc et al., 2017). With regard to metals, adult
anticipated anthropogenic modulation has been linked to intergenera- zebrafish exposed to 20 μg/L depleted uranium exhibited both sex- and
tional manifestations of physiological phenotypes. For example, ex- tissue-specific changes in global DNA methylation between 7 and
posure of damselfish, Acanthochromis polyacanthus, to acidic environ- 24 days (Gombeau et al., 2016). Exposure of adult zebrafish to 200 μg/L
ments mimicking ocean acidification levels has been shown to reverse of cadmium following differential rearing at temperatures of 26 °C and
the reaction to a chemical alarm cue within the exposed generation as 34 °C for 4 days, revealed a differential effect on methylation of four
well as in the F1 generation relocated to control conditions (Welch CpG sites in the promoter and first exon of hsp70 in the liver (Zheng
et al., 2014). Adult zebrafish exposed to microcystin-LR produce off- et al., 2017), providing evidence for intragenerational integration of
spring which exhibit diminished growth and reduced immune function specific DNA-methylation marks between naturogenic and anthro-
(Liu et al., 2014). Together, these and other emerging studies show that pogenic factors. Zebrafish exposure to 500 μg/L of lead resulted in re-
molecular epigenetic consequences in response to anthropogenic duction of dnmt3 and dnmt4 expression, which coincided with sig-
changes in environmental factors warrant further investigation, as these nificant decrease in global methylation levels in the embryo (Sanchez
markers may be predictive of physiological disruption or potential for et al., 2017). For industrial products, consequences of exposure to the
adaptation in the organism or its offspring. endocrine disrupting chemical BPA on DNA methylation have been
With regard to direct consequences of man-made aquatic pollutants investigated in significant detail in zebrafish, focusing largely on go-
on teleost epigenetics, several classes of contaminants have been linked nadal tissue indices due to observed inhibition of reproductive success.
to histone modifications intragenerationally. Chronic cadmium and For example, in female zebrafish exposed to 5 μg/L BPA, which as
copper exposure in a wild population of yellow perch, Perca flavescens, previously described exhibited ovarian histone modifications, increases
for example, revealed a metabolic and immune impairment as de- in ovarian dnmt1 and dnmt3 and concurrent decreases in dnmt4, dnmt6
termined at the hepatic transcriptome level (Pierron et al., 2011). These and dnmt7 transcripts were equally reported, suggesting action of
gene expression changes may have been driven through histone mod- multiple molecular epigenetic mechanisms in contaminant-induced
ifications, which were equally identified as being enriched in the genome regulation (Santangeli et al., 2016). Exposure of breeding pairs
transcriptomic dataset (Pierron et al., 2011). A study conducted in to BPA concentrations of 1 mg/L for a period of 15 days resulted in
European eels, Anguilla anguilla, which investigated environmental global hypomethylation in ovaries and testes, which coincided with
contaminants such as cadmium, mercury, polychlorinated bisphenyls decreased dnmt1 expression in female ovaries and a decrease in egg
(PCBs) and organochloride pesticides in a laboratory setting and fertilization at the organismal level (Laing et al., 2016). Similarly,
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global DNA methylation was decreased in zebrafish testes following long-term programming effects on these genes by DNA methylation in
exposure to 15 μg/L BPA for 7 days and in ovaries following exposure to response to embryonic exposure which may contribute to neurode-
the same concentration of BPA for 35 days (Liu et al., 2016b), sug- generative syndromes in adult zebrafish (Gao et al., 2017).
gesting that temporal dynamics in contaminant-induced DNA methy- The consequences of aquatic contaminants on teleost DNA methy-
lation may differ between sexes. In addition to differential regulation of lation have also been studied in inter- and transgenerational contexts,
dnmt transcript abundances, this study also identified BPA-dependent albeit to a much lesser extent. F1 and F2 generation embryos derived
regulation of tet transcripts, pointing to a role for both DNA methylation from adult females which had been subjected to 47 day and 32 day
and demethylation pathways in the effects of BPA on gonadal DNA exposures of 10 mg/kg MeHg or 20 μg/kg TCDD and mated with un-
methylation dynamics (Liu et al., 2016b). A gene promoter-specific exposed males, revealed no effect on global methylation, but modest
investigation of BPA effects on DNA methylation in zebrafish was changes in specific promoter methylation identified by MeDIP tiling
provided by Zhao et al. (2017b), who linked the induction of hepatic array (Olsvik et al., 2014). However, these marks generally did not
esr1 transcripts and of gonadal aromatase cyp19a1 transcripts in re- correlate to transcript changes as measured by microarray and real-time
sponse to a 21 day exposure of 500 and 1500 μg/L BPA to decreased RT-PCR, suggesting that other mechanisms may be involved in driving
promoter CpG methylation. In addition to these described peripheral the gene expression changes that underlie the observed cardiovascular
effects, BPA exposure in zebrafish also induced long-lasting changes in and neurological effects in the offspring of exposed female zebrafish
central regulation of the reproductive axis, as evidenced by the induc- (Olsvik et al., 2014). Importantly, this study provides evidence for
tion of embryonic transcript abundance of kiss1, gnrh3 and fshβ (Qiu contaminant-induced maternal inheritance of DNA methylation pat-
et al., 2016). However, epigenetic mechanisms, which may be re- terns in zebrafish, limiting the prediction that DNA inter- and trans-
sponsible for longer-term developmental effects on these targets, have generational DNA methylation patterns may be largely paternally in-
not been investigated in this study. Of note, these intra-generational herited (Jiang et al., 2013a; Potok et al., 2013; Kamstra et al., 2015a).
effects of BPA on central components of the endocrine axis of re- Similarly, a recent study in F1 and F2 generation larvae derived from F0
production do not appear to be restricted to zebrafish, as early devel- zebrafish, which had been exposed to 30 μM of mono(2-ethylhexyl)
opment BPA exposures equally affected gnrh3 neuronal developmental phthalate (MEHP) during early embryonic development (0–6 dpf; days
trajectories in Japanese medaka (Inagaki et al., 2016). Together, these post-fertilization), also challenges the paradigm of exclusive paternal
results suggest possible widespread developmental disruption by BPA, inheritance of DNA methylation patterns in response to contaminant
which similar to findings in mammals, is at least partially mediated by exposure (Kamstra et al., 2017). This is based on the finding that while
context-dependent epigenetic mechanisms (Kundakovic and a few transgenerationally stable DMRs, such as the hypermethylated
Champagne, 2011). However, the overall comparability of several cbfa2t2 locus, were identified in 6 dpf old embryos, its methylation
studies investigating molecular epigenetic effects in teleost fish are status in F0 sperm was found to be hypomethylated, suggesting non-
restricted by the choice of specific methods used, which can, as dis- paternal contributions. Another recent study in zebrafish revealed that
cussed for DNA methylation, affect sensitivity and resolution exposure of F0 zebrafish to MeHg resulted in hyperactivity and visual
(Kurdyukov and Bullock, 2016). Global DNA methylation is indirectly deficits in unexposed F2 descendants compared to control lineage ani-
assessed by measuring dnmt and tet mRNA abundance or the activity of mals, which correlated with DMRs of genes in F2 zebrafish sperm
their proteins, as well as directly by quantifying global DNA methyla- (Carvan et al., 2017). Because these genes were shown to be involved in
tion. Global DNA methylation, while easier to obtain, is less meaningful in neuroactive ligand receptor interaction and actin-cytoskeleton
than specific DNA methylation measurements, as it does not allow the modulation (Carvan et al., 2017), it was suggested that these “epimu-
linking of specific epigenetic marks to specific gene expression. This can tations” may be markers and mediators of the observed transgenera-
be addressed using higher resolution measurements including genome- tional physiological effects. However, the developmental fate of these
wide or gene-specific bisulfite conversion or MeDIP approaches. marks within a generation was not addressed in this study and it is
Pesticide exposures in the form of atrazine administered at a con- unclear whether these sperm ‘epimutations’ translated into conserved
centration of 30 μg/L throughout zebrafish embryonic development marks in somatic cells (Carvan et al., 2017). Finally, F0 zebrafish ex-
(1–72 hpf), demonstrated a significant decrease in global methylation, posed to 5–10 μM Benzo[a]pyrene between 6 and 120 hpf revealed
and a concomitant downregulation of dnmt4 and dnmt5 transcripts in decreased oxygen consumption and lower heart rates, a physiological
whole embryos (Wirbisky-Hershberger et al., 2017). Using a MeDIP phenotype that was equally present in the F2 offspring. These effects
sequencing approach, Qian et al. (2017) identified differentially regu- correlated with decreased total embryonic DNA methylation and re-
lated DNA methylation regions (DMRs) in embryonic DNA from zeb- duced transcript abundance of several dnmt paralogues in the F0 gen-
rafish that had been exposed to 800 μg/L fipronil between 6 and eration, an effect dependent on Ahr2 receptor recognition of Benzo[a]
120 hpf. In addition to different DNA methylation patterns that de- pyrene (Knecht et al., 2017). However, since epigenetic marks in ga-
pended on the enantiomer used, DMRs largely affected target genes metes were not profiled in this study, a possible contribution of mole-
involved in developmental cell signaling and cellular adhesion pro- cular epigenetic mechanisms for the transgenerational inheritance of
cesses, which correlated with observed developmental toxicity. Zebra- this physiological phenotype warrants future study. Overall, while there
fish exposed to 5 nM of the POP 2,3,7,8-tetrachlorodibenzo-p-dioxin is clear evidence for context-dependent DNA methylation in response to
between 4 and 5 hpf revealed differential regulation of dnmt transcripts, aquatic contaminants, the extent to which this contributes to observed
with upregulated dnmt1 and largely downregulated de novo dnmt3 phenotypes remains to be elucidated. Similarly, while there is evidence
paralogue transcripts. While these changes did not coincide with global for inter- and transgenerational inheritance of DNA methylation, cur-
changes in DNA methylation, they did result in CpG methylation rent evidence contradicts a mere paternal inheritance of paternal DNA
changes in specific ahr (aryl hydrocarbon receptor) target genes al- methylation patterns altered by contaminants. Future studies are
though this did not correspond to changes in ahr transcript abundance clearly needed to investigate the fate of contaminant-induced germ cell
(Aluru et al., 2015). Zebrafish exposed to the PAH benzo[a]pyrene DNA methylation as well as the inheritance of contaminant-induced
displayed an upregulation of dnmt1 and dnmt3a transcripts in embryos changes in gamete DNA methylation in somatic cells across develop-
immediately after exposure at 96 hpf, which persisted in the adult brain ment. At least at the level of gametes, the experiments described above
(Gao et al., 2017). Gene promoter specific DMR analysis via MeDIP clearly indicate the feasibility of gamete DNA methylation profiling
RNA-seq in conjunction with real-time RT-PCR measurement of target (Potok et al., 2013; Jiang et al., 2013a).
mRNA revealed that gucy2f and drd4 (genes involved in nervous system Context-dependent regulation of the miRNAome in tissues of a
development) were hypermethylated, and correlated with decreased variety of teleost fish exposed to aquatic contaminants has been de-
transcripts in embryo and adult brain (Gao et al., 2017). This suggests scribed for metals (Kure et al., 2013; Qiang et al., 2017),
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pharmaceuticals (Craig et al., 2014; Cameron et al., 2016), pesticides functionalization. This represents another avenue of research that will
(Wirbisky et al., 2016) and algal toxins (Brzuzan et al., 2016). These undoubtedly contribute to better understanding of basic teleost epige-
studies generally identify miRNAs at the transcriptome-level (e.g. mi- netics.
croarray, or small RNA sequencing) or individual miRNA level (real- Outside the immediate toolbox repertoire, epigenetic mark dy-
time RT-PCR) and correlate these miRNAs to mRNA abundance of in namics and functionality reveal both similarities and differences com-
silico predicted target genes. For example, the liver of adult zebrafish pared to better studied invertebrate or mammalian models. With regard
exposed to the pharmaceutical fluoxetine revealed an upregulation of to histone modifications, research largely suggests a conservation of
dre-let-7d and dre-miR-140-5p correlated with a downregulation of its histone marks, which, however remain almost exclusively characterized
predicted targets, the α1 and α2 subunits of the energy sensor ampk across baseline development in zebrafish and largely omit comparative
(Craig et al., 2014). However, this study and current studies in general studies in response to environmental stimuli in this species. In spite of
have not mechanistically addressed the functionality of these predicted its feasibility, as recently demonstrated in rainbow trout (Marandel
miRNA-target relationships, and future studies using in vitro approaches et al., 2016), histone modifications in other teleost species remain un-
such as transfection assays with miRNA agonists and antagonists or derstudied. In contrast, DNA methylation dynamics in zebrafish are
luciferase assays based on 3′UTR-containing plasmids are clearly war- studied in baseline development as well as in response to environmental
ranted in teleost fish in order to substantiate physiologically meaningful stimuli, but reveal important functional differences in location and
miRNA-mRNA interactions in detail. As described, inter- and transge- generational transmission. Thus, future genome-wide correlative stu-
nerational effects of aquatic contaminants are increasingly reported at dies are needed to improve our understanding of DNA methylation loci,
the organismal level in zebrafish whose ancestors had been exposed to as DNA methylation in CpG sites in promoter regions has not always
aquatic contaminants. Similar to histone modifications, however, and been reported to be the best predictor of gene expression profiles.
in spite of the technical feasibility to profile microRNAs in fish gametes Emerging studies employing CRISPR-Cas9 based constructs containing
(Jia et al., 2015; Ma et al., 2015; Presslauer et al., 2017), no studies to catalytic components of Dnmt (Vojta et al., 2016; Lei et al., 2017), or
date have investigated aquatic contaminant-induced changes in Tet proteins (Morita et al., 2016) have been shown to specifically me-
miRNAs in fish gametes. These studies are clearly warranted, given that thylate and demethylate genomic target sequences in vitro and in vivo,
alterations in the miRNAome in stress-exposed rats have been me- and may allow this question to be addressed functionally by site-spe-
chanistically linked to programming the stress-axis in their offspring, cific methylation of promoters, introns, exons, and putative enhancers
providing evidence for miRNA-mediated intergenerational inheritance. in zebrafish.
(Rodgers et al., 2013; Rodgers et al., 2015). Finally, miRNA networks appear to have undergone extensive re-
wiring in teleost fish compared to well-studied mammalian models,
5. Future basic research directions and possible translational suggesting possible functional differences at higher levels of biological
research benefits organization. Currently miRNAs remain the only molecular epigenetic
mark that can be directly modulated experimentally with high speci-
Based on the reviewed information, we will here integrate emerging ficity, for example through antagomiRs, which have been used in an
insights to propose future directions for research in the field of teleost increasing number of teleost fish species in vitro and in vivo (Mennigen,
fish epigenetics. The first section will identify research areas of priority 2015). Conversely, functional consequences of methylation and histone
in teleost epigenetics and critically address the utilization and current modification on individual loci may currently only indirectly be ad-
limitations of current experimental designs and methodologies in the dressed either by global, non-specific pharmacological modulation of
field. The second section will highlight how the developing area of basic epigenetic marks, or by mimicking consequences of specific epigenetic
research in teleost epigenetics can inform translational research related by targeting the regulated gene locus using previously described
primarily to aquaculture and aquatic toxicology, but also human health. CRISPR-Cas9 or morpholino-based techniques. In contrast to antag-
omiR-based miRNA modulation, such modulation will be indirect and
5.1. Basic research priorities for teleost epigenetics and experimental less precise, thus limiting our understanding of the functional con-
considerations sequences of specific epigenetic marks at the DNA level. Regardless of
the specific epigenetic mechanism studied, previously described
At the basic research level, epigenetic research in teleost fish is genome duplication events have also resulted in the retention of many
currently largely focused on the zebrafish model, which is considered to protein coding genes targeted by epigenetic regulation, adding further
be well-suited to link molecular epigenetics to the developmental and complexity to teleost epigenetics. Therefore, as indicated by some
transgenerational emergence of physiological phenotypes given its se- pioneering studies, the role of epigenetic mechanisms in the regulation
quenced and comparatively well-annotated genome, and available tools of teleost paralogues warrants further study, as this will improve our
for genome-wide or gene-specific profiling and genetic manipulation. understanding of how teleost fish successfully evolved to inhabit di-
Even within the zebrafish model, however, there is a need to increase verse ecological niches.
precision in our understanding of epigenetic pathways at the molecular Experimentally, four approaches may prove especially useful to
level in order to link molecular function to physiological relevance. improve our capacity to link epigenetic marks to gene expression and,
While this can be seen as a historically rooted ‘schism’ between mole- ultimately, physiological phenotypes. Firstly, epigenetic marks are
cular and developmental or phenotypic understanding of epigenetics, currently widely studied in isolation, which, in addition to potential
this becomes even more important in zebrafish, where clear differences differences in the genomic location of regulatory epigenetic marks,
in the epigenetic toolbox, dynamics and genomic location of epigenetic may, at least in part, explain the often poor correlations between per-
marks, and their inter- and transgenerational inheritance exist. For missive or repressive epigenetic marks and gene expression. For ex-
example, the roles of teleost-specific dnmt3b paralogues and/or teleost- ample, as in mammals, interaction between all major molecular epi-
specific miRNAs remain uncharacterized, and should be addressed by genetic mechanisms has been described in teleost fish correlationally as
CRISPR-Cas9 or morpholino-based approaches in future studies, which well as mechanistically. For example, correlative evidence for cross-talk
have successfully been employed not only in zebrafish, but increasingly between histone modifications and DNA methylation stem from studies
in salmoniform species (Wargelius et al., 2016). Additional diversity in in zebrafish, where CG-rich promoters have been shown to combine
the epigenetic toolbox stems from the fact that several components hypomethylation and H3K4 trimethylation marks, indicative of con-
have been retained as paralogues in subsequent rounds of genome certed action permissive of gene expression (Andersen et al., 2012).
duplication, and as suggested by our in silico analysis of salmoniform Conversely, a strong antagonism between DNA methylation and the
xpo5, it is possible that these paralogues have undergone sub- histone mark H3K27me3, has been identified at the genome level across
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three development stages (dome, 24 hpf, 48 hpf) in early zebrafish de- susceptible to context- and germline- dependent epigenetic repro-
velopment (de la Calle Mustienes et al., 2015). Alongside correlative gramming which may alter the emergence of physiological phenotypes
analysis of epigenetic marks at the genome level, molecular compo- across the life-cycle and generations. This will allow, for example,
nents mediating crosstalk between epigenetic marks are beginning to testing of the hypotheses that exposure to a single stimulus translates to
emerge as well. For example, Dnmt1 knockdown-mediated defects in longer propagation of altered physiological phneotypes, or that germ-
development of intestine, exocrine pancreas, and retina coincided with line dependent epigenetics alter physiological responses of future gen-
reduced H3K9me3 levels, which are established by Suv39h1. Knock- erations to separate environmental stimuli acting by context-dependent
down of Suv39h1 and rescue experiments introducing functional epigenetics. In this context, it will be increasingly important to clearly
Suv39h1 in Dnmt1 knockout fish clearly revealed that the histone- separate transgenerational from context-dependent effects, for example
modification enzyme Suv39h1 mediates Dnmt1 effects on organogen- by excluding the possibility of maternal transfer of lipophilic hormones
esis (Rai et al., 2006). Equally in zebrafish, it has been determined that (Jeffrey and Gilmour, 2016) or contaminants (Aluru et al., 2010) in
the H3 demethylase kdmb2 recognizes demethylated CpG sites, con- oocytes through the use of analytical chemistry methods.
ferring specificity to its mediated histone modifications (Farcas et al., Thirdly, an a priori understanding of genetic background and phy-
2012). Evidence for crosstalk between DNA level epigenetic modifica- siological states is equally warranted, as specific teleost strains
tions and microRNAs remains correlational, as seen in studies using (Burgerhout et al., 2017) or endogenous factors may factors regulate
zebrafish and rainbow trout. For example, a strong occupancy of pri- epigenetic marks in addition to environmental factors (Fig. 1). The
miRNA promtors by H3K4me3 has been observed in zebrafish embry- importance of endogenous factors is exemplified by the estrogen-de-
ogenesis (Nepal et al., 2016), while in rainbow trout, a recent gene pendent regulation of the abundant and liver specific miRNA-122 in
expression study coupled with in silico predictions suggested an evolu- zebrafish (Cohen and Smith, 2014; Cohen et al., 2017), which may
tionary deeply conserved crosstalk between miRNA-29 and a dnmt1 introduce sex-specific functional differences in the nutritional regula-
paralogue (Kuc et al., 2017). Together, these studies clearly point to tion and metabolic function of miRNA-122 in fish (Mennigen, 2015).
crosstalk between epigenetic mechanisms in teleost fish. Furthermore, Indeed, widespread sexually dimorphic miRNA expression profiles have
emerging molecular epigenetic mechanisms, such as long non-coding been identified in developing zebrafish (Vaz et al., 2015), emphasizing
RNAs, which confer specificity to recruitment of the epigenetic ma- that genetic or endogenous endocrine signals contribute to environ-
chinery at the DNA level (Mercer et al., 2009), are increasingly char- mental regulation of epigenetic marks in teleost fish.
acterized in teleost models, including zebrafish (Dhiman et al., 2015), Finally, because the large and diverse infraclass of teleost fish allows
rainbow trout (Wang et al., 2016a; Al-Tobasei et al., 2016) and Atlantic physiological systems to be studied in a variety of environmental and
salmon (Boltaña et al., 2016). An additional example is the recent de- evolutionary contexts, future research should take advantage of the
scription of methylated adenosines (6 mA) present in zebrafish mRNA increasingly available teleost genome and transcriptome resources
during embryogenesis (Liu et al., 2016a), which have now been shown (Mennigen, 2015) to fully exploit the potential of this infraclass for
to play a role in maternal mRNA clearance (Zhao et al., 2017a) and comparative epigenetics. The Krogh principle has been historically
early cell fate determination (Zhang et al., 2017b). Both examples applied to many fish species, and will undoubtedly lead to better in-
testify to the dynamic nature of the field of teleost epigenetics. sights into how epigenetics can govern physiological systems in extreme
A second experimental consideration addresses an important aspect environmental conditions across the life cycle, between generations and
of the epigenetic definition, that of spatiotemporal control. With regard finally at the evolutionary scale. Indeed, outside the most widely stu-
to location, current information in teleosts clearly suggests that epige- died zebrafish model, genome-wide and gene-specific approaches to
netic mark dynamics change in tissue specific development, and future profile histone modification, DNA methylation and non-coding RNA
studies are therefore warranted to improve cell population-specific re- abundance are now used in additional models, such as the rainbow
solutions. The described need to identify the fate of epigenetic marks of trout (Mennigen, 2015; Seiliez et al., 2015; Baerwald et al., 2016;
PGCs represents an excellent example, and given that GFP-based cell Marandel et al., 2016; Juanchich et al., 2016; Al-Tobasei et al., 2016).
sorting of PGCs has been achieved in teleost fish (Fan et al., 2008; This has been largely driven by the publication of the rainbow trout
Kobayashi et al., 2004), future studies may utilize this technique to genome (Berthelot et al., 2014), showing that genomic resources, rather
achieve better specificity. With regard to temporal aspects of epigenetic than technical approaches themselves, represent bottlenecks in ex-
regulation in teleost fish, current studies generally link epigenetic panding teleost epigenetic research to additional species.
marks and gene expression profiles at a single time point, which may
reduce correlations between specific epigenetic marks and gene ex- 5.2. Translational aspects of teleost epigenetics
pression by ignoring the temporal relationships between the establish-
ment of epigenetic marks and gene expression. Therefore, similar to a In addition to the discussed implications for comparative phy-
previous suggestion to resolve observed discrepancies between mRNA siology, the emerging field of teleost epigenetics holds promise for three
and protein abundance in teleost fish tissues sampled at single time- principal areas of applied research, specifically aquaculture, ecotox-
points (Popesku et al., 2010), detailed time-series experiments are icology and human disease. We here briefly explore potential applied
therefore warranted for epigenetic marks. Since cost likely represents a benefits of teleost epigenetic research in each of the three areas.
limiting factor, the identification of consistently altered mRNA abun-
dance of specific targets in response to experimental conditions may be 5.2.1. Aquaculture
identified from deposited transcriptomic time-series datasets, allowing In the context of aquaculture, the potential for teleost epigenetics
pre-screening of specific genes for subsequent determination of epige- has been recognized and for an in-depth discussion, the reader is di-
netic marks. In addition to developmental stages, this also applies to rected to recent reviews on the subject (Li and Leatherland, 2012;
inter- and transgenerational timescales, for which the characterization Moghadam et al., 2015; Granada et al., 2017; Gavery and Roberts,
of epigenetic marks in gametes and embryos (and specifically their 2017). For the purpose of the current review, we will limit our dis-
PGCs) before and after MZA are especially warranted. Experimentally, cussion to four principal translational benefits. Firstly, the under-
very few studies currently address paternal and maternal contributions standing of developmental progression of epigenetic marks in con-
in teleost fish, and experimental outcross designs employing experi- junction with ontogenetic development allows for the development of
mentally treated males and females mated with wild types of the op- meaningful markers, which given the strong role of epigenetic marks in
posite sex up to the F2 generation (Fig. 2) will allow prioritization of the controlling spatio-temporal gene expression, may represent a way to
investigation of epigenetic marks in sperm and eggs. Transgenerational identify epigenetic biomarkers predictive of future tissue development,
experiments will also address specific developmental windows growth rates, food conversion, immune competence, reproductive
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success or other physiological traits relevant to aquaculture operations. teleost fish in biomedical research, with emerging models for a plethora
Such marks are currently investigated not only at baseline, but also in of human conditions (Lieschke and Currie, 2007). Especially zebrafish
programming approaches using developmental exposure to environ- hold promise with regard to research addressing molecular epigenetic
mental factors such as nutrition, temperature, or hypoxia in an effort to determinants of human disease, however, it is important to distinguish
modulate specific traits in adult aquaculture species directly. Such re- translational possibilities and limitations. For example, as discussed in
search has especially been conducted in the context of nutritional this review, clear differences with regard to molecular epigenetic me-
programming of aquaculture species (Geurden et al., 2014; Liu et al., chanisms exist between teleost fish and mammalian models, ex-
2017a; Liu et al., 2017b; Panserat et al., 2017) or relevant model spe- emplified by largely different miRNA-mRNA networks and genome
cies (Ulloa et al., 2014; Rocha et al., 2014; Rocha et al., 2015). Sec- methylation dynamics. Therefore, the specific translation of specific
ondly, the identification of epigenetic markers may uncover molecular epigenetic signatures to human disease will likely prove challenging.
bottlenecks that may limit specific traits of importance in aquaculture, The comparative approach in elucidating differences in epigenetic
such as macronutrient-utilization. This is exemplified by glucose in- molecular regulation may however also provide opportunities to in-
tolerance in rainbow trout, which recent evidence has linked to both crease our understanding of the functionality of human epigenetic
DNA level epigenetic marks (Marandel et al., 2016) and hepatic mi- marks. For example, the comparative probing of miRNA networks in
croRNAs (Mennigen et al., 2014a). Thus, uncovering novel epigenetic teleost fish, which are predicted to target only 10% of common mRNA
targets for nutritional modulation, for example, may lead to specific targets compared to mammalian models (Xu et al., 2013), may help to
approaches targeting epigenetic bottlenecks to improve nutrient utili- identify the most important, evolutionarily conserved miRNA-mRNA
zation. Thirdly, the identification of epigenetic markers may provide an relationships that mediate physiological responses, which often remain
additional dimension to complement purely genetic selection for unknown in mammals (Mennigen, 2015). Along the same vein, com-
breeding. For example, epigenetic marks are beginning to be char- parative analysis of similar miRNA expression patterns in response to
acterized in eggs (Ma et al., 2012; Ma et al., 2015) and cryopreserved specific environmentally stimuli may equally prove of interest.
sperm (de Mello et al., 2017) of aquaculture species, and may be used to In addition to a direct translational context of specific epigenetic
predict developmental and multigenerational trajectories for specific marks, the zebrafish model allows to screen for global epigenetic ac-
traits in the future, pending a better understanding of temporal dy- tivity of specific compounds in vivo, as exemplified by the zebraRDM
namics and functional consequences of these marks. Finally, a recent line that allows to visualize DNA methylation dynamics via knockin of
study revealed that the epigenetic marks, and specifically the methy- an mCherry-fused methyl-CpG binding domain (MBD) probe driven by
lome in Pacific Atlantic salmon, was significantly affected by the the actin2 promoter (Zhang et al., 2017a). Such tools will likely prove
rearing environment in hatchery origin fish released into the wild (Le useful not only to screen for environmental factors that might con-
Luyer et al., 2017), which may contribute to reduced fitness of fish tribute to disease etiology, but also to screen for novel therapeutics
escaping aquaculture operations. Thus, epigenetic marks and their affecting global DNA methylation.
possible transgenerational transfer in offspring between hatchery At the organismal level, zebrafish represent an excellent model to
reared and wild fish populations may address possible environmental translate epidemiological evidence indicative of epigenetic disease
consequences of fish released from aquaculture settings. etiology into testable hypotheses in a vertebrate model. For example,
zebrafish are increasingly used as model for metabolic disease (Seth
5.2.2. Aquatic toxicology et al., 2013; Santoro, 2014; Schlegel and Gut, 2015), as they exhibit
In the field of aquatic toxicology, several reviews on the topic al- largely conserved metabolic pathways involved in regulating energy
ready testify to the translational potential of teleost epigenetics balance (Forlano and Cone, 2007; Craig and Moon, 2011). While in-
(Vandegehuchte and Janssen, 2011; Kamstra et al., 2015a; Aluru, dividual hypotheses proposed for metabolic disease, such as the life-
2017). We particularly highlight the large predictive potential of epi- style hypothesis (Seaman, 2013) and the environmental obesogen hy-
genetic marks in the context of aquatic toxicology. The identification of pothesis (Baillie-Hamilton, 2002; Grün and Blumberg, 2006) have been
epigenetic signatures in gametes, as well as early embryonic stages, in tested individually in the zebrafish (Oka et al., 2010; Meguro et al.,
response to aquatic contaminants may, when coupled with detailed 2015; Tingaud-Sequeira et al., 2011; Riu et al., 2014), this model allows
understanding of temporal consequences of specific marks established integration of these hypotheses across developmental and generational
by basic research, help to better predict physiological consequences and timescales in the context of the developmental origin of adult disease
fitness in later developmental stages and offspring. This is true for hypothesis (Barker and Fall, 1990) in a well-characterized vertebrate
changes in physiological homeostasis at baseline, but is especially re- model. While specific molecular epigenetic marks may differ compared
levant in response to additional environmental changes relevant to to mammals, such studies conducted in the historical context of epi-
teleost fishes, which are equally affected through anthropogenic ac- genetics emphasizing development and phenotypic emergence, rather
tivity. Current studies in teleost fish have, to a large extent, yet to ex- than specific molecular mechanisms, hold significant promise to im-
amine integrated consequences of aquatic contaminant exposure in prove our understanding of human disease etiology across large time-
conjunction with additional homeostatic challenges, caused by a scales, and may allow us to identify specific germ-line dependent pa-
change in factors affecting the aquatic environment, for example ternal or maternal ancestral contribution to metabolic disease, either
through global warming or (associated) changes in water chemistry. independently or in addition to an additional context-dependent chal-
Importantly, properly conducted experiments can furthermore, as de- lenge on energy homeostasis. Indeed, various assays to probe metabolic
scribed, help to delineate specific parental contributions, to physiolo- phenotypes by addressing key contributors of energy balance home-
gical adaptation or disruption across generations, and have therefore ostasis at the organismal level in zebrafish, such as food intake (Hirano
important ramifications towards more targeted intervention in con- et al., 2012; Nishiguchi et al., 2012), metabolic rate (Makky et al.,
servation efforts. 2008; Stackley et al., 2011; Dalman et al., 2013), and locomotory ac-
tivity (Lange et al., 2013), now allow high throughput analysis, and can
5.2.3. Human disease be coupled with molecular advantages of the zebrafish model. Thus, in
Because teleost fish exhibit, as the largest vertebrate infraclass, an concrete terms, the zebrafish model would allow to us to test, for ex-
immense diversity in their physiological adaptations to specific en- ample, the hypothesis that ancestral populations exposed to obesogens
vironments, individual teleost species have historically been used as may render offspring more susceptible to metabolic disruption in re-
comparative model to study human disease (Schartl, 2014). More re- sponse to dietary challenges.
cently, the well characterized genetic and developmental versatility of
the zebrafish model have resulted in an unprecedented utilization of
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