Mcm2 promotes stem cell differentiation via its ability to bind H3-H4

  1. Xiaowei Xu
  2. Xu Hua
  3. Kyle Brown
  4. Xiaojun Ren
  5. Zhiguo Zhang  Is a corresponding author
  1. Columbia University Medical Center, United States
  2. University of Colorado Denver, United States

Abstract

Mcm2, a subunit of the Mcm2-7 helicase best known for its role in DNA replication, contains a histone binding motif that facilitates the transfer of parental histones following DNA replication. Here we show that Mcm2 is important for the differentiation of mouse embryonic stem (ES) cells. The Mcm2-2A mutation defective in histone binding shows defects in silencing of pluripotent genes and the induction of lineage specific genes. The defects in the induction of lineage specific genes in the mutant cells are likely, at least in part, due to reduced binding to Asf1a, a histone chaperone that binds Mcm2 and is important for nucleosome disassembly at bivalent chromatin domains containing repressive H3K27me3 and active H3K4me3 modifications during differentiation. Mcm2 localizes at transcription starting sites and the binding of Mcm2 at gene promoters is disrupted in both Mcm2-2A ES cells and neuro-precursor cells (NPCs). Reduced Mcm2 binding at bivalent chromatin domains in Mcm2-2A ES cells correlates with decreased chromatin accessibility at corresponding sites in NPCs. Together, our studies reveal a novel function of Mcm2 in ES cell differentiation, likely through manipulating chromatin landscapes at bivalent chromatin domains.

Data availability

Raw and processed sequencing data generated in the course of this study can be accessed via the GEO database with accession number: GSE203272.

The following data sets were generated

Article and author information

Author details

  1. Xiaowei Xu

    Institute for Cancer Genetics, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6050-9536
  2. Xu Hua

    Institute for Cancer Genetics, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9775-4129
  3. Kyle Brown

    Department of Chemistry, University of Colorado Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiaojun Ren

    Department of Chemistry, University of Colorado Denver, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3931-7625
  5. Zhiguo Zhang

    Department of Pediatrics, Columbia University Medical Center, New York, United States
    For correspondence
    zz2401@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9451-2685

Funding

National Institute of General Medical Sciences (R35118015)

  • Zhiguo Zhang

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

Reviewing Editor

  1. Weiwei Dang, Baylor College of Medicine, United States

Version history

  1. Received: June 9, 2022
  2. Preprint posted: June 17, 2022 (view preprint)
  3. Accepted: November 9, 2022
  4. Accepted Manuscript published: November 10, 2022 (version 1)
  5. Version of Record published: November 22, 2022 (version 2)

Copyright

© 2022, Xu 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.

Metrics

  • 993
    Page views
  • 182
    Downloads
  • 6
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiaowei Xu
  2. Xu Hua
  3. Kyle Brown
  4. Xiaojun Ren
  5. Zhiguo Zhang
(2022)
Mcm2 promotes stem cell differentiation via its ability to bind H3-H4
eLife 11:e80917.
https://doi.org/10.7554/eLife.80917

Share this article

https://doi.org/10.7554/eLife.80917