Cohesin-dependence of neuronal gene expression relates to chromatin loop length

  1. Lesly Calderon
  2. Felix D Weiss
  3. Jonathan A Beagan
  4. Marta S Oliveira
  5. Radina Georgieva
  6. Yi-Fang Wang
  7. Thomas S Carroll
  8. Gopuraja Dharmalingam
  9. Wanfeng Gong
  10. Kyoko Tossell
  11. Vincenzo de Paola
  12. Chad Whilding
  13. Mark A Ungless
  14. Amanda G Fisher
  15. Jennifer E Phillips-Cremins  Is a corresponding author
  16. Matthias Merkenschlager  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Bonn, Germany
  3. University of Pennsylvania, United States
  4. Rockefeller University, United States

Abstract

Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in mouse primary cortical neurons. Immediate early genes remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the Immediate early gene Fos formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterised by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend on cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts.

Data availability

RNAseq and 5C data generated in this study have been deposited at Gene Expression Omnibus under accession number GSE172429

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Lesly Calderon

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5253-7369
  2. Felix D Weiss

    Institute of Innate Immunity, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Jonathan A Beagan

    Department of Bioengineering, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Marta S Oliveira

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Radina Georgieva

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Yi-Fang Wang

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Thomas S Carroll

    Bioinformatics Resouce Center, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gopuraja Dharmalingam

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Wanfeng Gong

    Department of Bioengineering, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kyoko Tossell

    Institute of Clinical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Vincenzo de Paola

    Institute of Clinical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Chad Whilding

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Mark A Ungless

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. Amanda G Fisher

    MRC London Institute of Medical Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Jennifer E Phillips-Cremins

    Department of Bioengineering, University of Pennsylvania, Philadelphia, United States
    For correspondence
    jcremins@seas.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
  16. Matthias Merkenschlager

    Institute of Clinical Sciences, Imperial College London, London, United Kingdom
    For correspondence
    matthias.merkenschlager@lms.mrc.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2889-3288

Funding

Medical Research Council

  • Matthias Merkenschlager

Wellcome Trust (099276/Z/12/Z)

  • Matthias Merkenschlager

European Molecular Biology Organization (ALTF 1047-2012)

  • Lesly Calderon

Human Frontiers in Science Program (LT00427/2013)

  • Lesly Calderon

National Institutes of Health (1R01-MH120269)

  • Jennifer E Phillips-Cremins

National Institutes of Health (1DP1OD031253)

  • Jennifer E Phillips-Cremins

National Institutes of Health (1R01-NS114226)

  • Jennifer E Phillips-Cremins

4D Nucleome Common Fund (1U01DK127405)

  • Jennifer E Phillips-Cremins

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Laboratory bred mice of the appropriate genotype were maintained under SPF conditions and 12h light/dark cycle. Embryos were used to derive cells and tissues. Ethical approval was granted by the Home Office, UK, and the Imperial College London Animal Welfare and Ethical Review Body (AWERB).

Reviewing Editor

  1. Jeremy J Day, University of Alabama at Birmingham, United States

Publication history

  1. Preprint posted: February 24, 2021 (view preprint)
  2. Received: December 20, 2021
  3. Accepted: April 26, 2022
  4. Accepted Manuscript published: April 26, 2022 (version 1)
  5. Version of Record published: May 13, 2022 (version 2)

Copyright

© 2022, Calderon et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lesly Calderon
  2. Felix D Weiss
  3. Jonathan A Beagan
  4. Marta S Oliveira
  5. Radina Georgieva
  6. Yi-Fang Wang
  7. Thomas S Carroll
  8. Gopuraja Dharmalingam
  9. Wanfeng Gong
  10. Kyoko Tossell
  11. Vincenzo de Paola
  12. Chad Whilding
  13. Mark A Ungless
  14. Amanda G Fisher
  15. Jennifer E Phillips-Cremins
  16. Matthias Merkenschlager
(2022)
Cohesin-dependence of neuronal gene expression relates to chromatin loop length
eLife 11:e76539.
https://doi.org/10.7554/eLife.76539

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