STAG2 promotes the myelination transcriptional programin oligodendrocytes

  1. Ningyan Cheng
  2. Guanchen Li
  3. Mohammed Kanchwala
  4. Bret M Evers
  5. Chao Xing
  6. Hongtao Yu  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States
  2. Westlake University, China

Abstract

Cohesin folds chromosomes via DNA loop extrusion. Cohesin-mediated chromosome loops regulate transcription by shaping long-range enhancer-promoter interactions, among other mechanisms. Mutations of cohesin subunits and regulators cause human developmental diseases termed cohesinopathy. Vertebrate cohesin consists of SMC1, SMC3, RAD21, and either STAG1 or STAG2. To probe the physiological functions of cohesin, we created conditional knockout (cKO) mice with Stag2 deleted in the nervous system. Stag2 cKO mice exhibit growth retardation, neurological defects, and premature death, in part due to insufficient myelination of nerve fibers. Stag2 cKO oligodendrocytes exhibit delayed maturation and downregulation of myelination-related genes. Stag2 loss reduces promoter-anchored loops at downregulated genes in oligodendrocytes. Thus, STAG2-cohesin generates promoter-anchored loops at myelination-promoting genes to facilitate their transcription. Our study implicates defective myelination as a contributing factor to cohesinopathy and establishes oligodendrocytes as a relevant cell type to explore the mechanisms by which cohesin regulates transcription.

Data availability

The RNA-seq, scRNA-seq, ChIP-seq, and Hi-C datasets generated and analyzed during the current study are available in the GEO repository, with the accession number GSE186894.

The following data sets were generated

Article and author information

Author details

  1. Ningyan Cheng

    Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Guanchen Li

    School of Life Sciences, Westlake University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Mohammed Kanchwala

    Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bret M Evers

    Division of Neuropathology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5686-0315
  5. Chao Xing

    Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1838-0502
  6. Hongtao Yu

    Westlake Laboratory of Life Sciences and Biomedicine, Westlake University, Hangzhou, Zhejiang Province, China
    For correspondence
    yuhongtao@westlake.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8861-049X

Funding

National Natural Science Foundation of China (Project 32130053)

  • Hongtao Yu

National Institutes of Health (1R01GM124096)

  • Hongtao Yu

Cancer Prevention and Research Institute of Texas (RP160667-P2)

  • Hongtao Yu

Welch Foundation (I-1441)

  • Hongtao Yu

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

Reviewing Editor

  1. Adèle L Marston, University of Edinburgh, United Kingdom

Ethics

Animal experimentation: All animals were handled in accordance with institutional guidelines of the Institutional Animal Care and Use Committee (IACUC; AAALAC unit number 000673) of University of Texas (UT) Southwestern Medical Center under the animal protocol number (APN) 102335.

Version history

  1. Preprint posted: October 12, 2021 (view preprint)
  2. Received: February 12, 2022
  3. Accepted: August 11, 2022
  4. Accepted Manuscript published: August 12, 2022 (version 1)
  5. Version of Record published: September 1, 2022 (version 2)

Copyright

© 2022, Cheng 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. Ningyan Cheng
  2. Guanchen Li
  3. Mohammed Kanchwala
  4. Bret M Evers
  5. Chao Xing
  6. Hongtao Yu
(2022)
STAG2 promotes the myelination transcriptional programin oligodendrocytes
eLife 11:e77848.
https://doi.org/10.7554/eLife.77848

Share this article

https://doi.org/10.7554/eLife.77848

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