Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Structural elements facilitate extreme long-range gene regulation at a human disease locus

Liang-Fu Chen, View ORCID ProfileHannah Katherine Long, Minhee Park, Tomek Swigut, Alistair Nicol Boettiger, Joanna Wysocka
doi: https://doi.org/10.1101/2022.10.20.513057
Liang-Fu Chen
aDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hannah Katherine Long
aDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Hannah Katherine Long
Minhee Park
bDepartment of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tomek Swigut
aDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Alistair Nicol Boettiger
bDepartment of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: boettiger@stanford.edu wysocka@stanford.edu
Joanna Wysocka
aDepartment of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
bDepartment of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
cInstitute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
dHoward Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: boettiger@stanford.edu wysocka@stanford.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Summary

Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 megabases. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. While we observed pronounced changes in locus topology between cell-types, analysis of single chromatin fiber traces revealed that these ensemble-average differences arise not from the presence of cell-type unique conformations, but through changes in frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which are positioned near its 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 multiloop, centrally clustered geometry, suggesting a mechanism for gene regulation over ultralong ranges.

Four short bullet points that convey the key message of the paper SOX9 domain topology dynamically changes during a developmental transition

Structural elements promote TAD-wide interactions, stripe formation and transcription

Structural elements are CTCF-dependent and situated centrally in the 3D TAD structure

Polymer simulations of multi-loop model best recapitulate topological features

Competing Interest Statement

J.W is a paid member of Camp4 and Paratus Biosciences scientific advisory boards.

Footnotes

  • ↵* Joint first authors

  • Abbreviations

    (NCC)
    neural crest cell
    (CNCC)
    cranial neural crest cell
    (PRS)
    Pierre Robin sequence
    (TAD)
    topologically associating domain
    (ORCA)
    optical reconstruction of chromatin architecture
    (SSE)
    stripe-associated structural element
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
    Back to top
    PreviousNext
    Posted October 21, 2022.
    Download PDF
    Email

    Thank you for your interest in spreading the word about bioRxiv.

    NOTE: Your email address is requested solely to identify you as the sender of this article.

    Enter multiple addresses on separate lines or separate them with commas.
    Structural elements facilitate extreme long-range gene regulation at a human disease locus
    (Your Name) has forwarded a page to you from bioRxiv
    (Your Name) thought you would like to see this page from the bioRxiv website.
    CAPTCHA
    This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
    Share
    Structural elements facilitate extreme long-range gene regulation at a human disease locus
    Liang-Fu Chen, Hannah Katherine Long, Minhee Park, Tomek Swigut, Alistair Nicol Boettiger, Joanna Wysocka
    bioRxiv 2022.10.20.513057; doi: https://doi.org/10.1101/2022.10.20.513057
    Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
    Citation Tools
    Structural elements facilitate extreme long-range gene regulation at a human disease locus
    Liang-Fu Chen, Hannah Katherine Long, Minhee Park, Tomek Swigut, Alistair Nicol Boettiger, Joanna Wysocka
    bioRxiv 2022.10.20.513057; doi: https://doi.org/10.1101/2022.10.20.513057

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
    • Tweet Widget
    • Facebook Like
    • Google Plus One

    Subject Area

    • Molecular Biology
    Subject Areas
    All Articles
    • Animal Behavior and Cognition (4095)
    • Biochemistry (8786)
    • Bioengineering (6493)
    • Bioinformatics (23386)
    • Biophysics (11766)
    • Cancer Biology (9167)
    • Cell Biology (13290)
    • Clinical Trials (138)
    • Developmental Biology (7422)
    • Ecology (11386)
    • Epidemiology (2066)
    • Evolutionary Biology (15119)
    • Genetics (10413)
    • Genomics (14024)
    • Immunology (9145)
    • Microbiology (22108)
    • Molecular Biology (8793)
    • Neuroscience (47445)
    • Paleontology (350)
    • Pathology (1423)
    • Pharmacology and Toxicology (2483)
    • Physiology (3711)
    • Plant Biology (8063)
    • Scientific Communication and Education (1433)
    • Synthetic Biology (2215)
    • Systems Biology (6021)
    • Zoology (1251)