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Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.

Author information

Affiliations

  • 1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
      Authors
    • Chen LF 1
    • Long HK 1
    • Swigut T 1
    (3 authors)
  • 2. Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
      Authors
    • Park M 2
    • Boettiger AN 2
    (2 authors)
  • 3. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
      Authors
    • Wysocka J 3
    (1 author)

ORCIDs linked to this article

Molecular Cell, 29 Mar 2023, 83(9):1446-1461.e6
https://doi.org/10.1016/j.molcel.2023.03.009 PMID: 36996812 

A comment on this article appears in "A party for transcription: Multiway interactions of enhancers and promoters." Mol Cell. 2023 May 18;83(10):1542-1544. doi: 10.1016/j.molcel.2023.04.027. This article is based on a previously available preprint.

Abstract 

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.molcel.2023.03.009

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Funding 

Funders who supported this work.

NIGMS NIH HHS (2)

Wellcome Trust (1)