Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3

  1. Junhao Li
  2. Antonio Pinto-Duarte
  3. Mark Zander
  4. Michael S Cuoco
  5. Chi-Yu Lai
  6. Julia Osteen
  7. Linjing Fang
  8. Chongyuan Luo
  9. Jacinta D Lucero
  10. Rosa Gomez-Castanon
  11. Joseph R Nery
  12. Isai Silva-Garcia
  13. Yan Pang
  14. Terrence J Sejnowski
  15. Susan B Powell
  16. Joseph R Ecker  Is a corresponding author
  17. Eran A Mukamel  Is a corresponding author
  18. M Margarita Behrens  Is a corresponding author
  1. University of California, San Diego, United States
  2. Salk Institute for Biological Studies, United States
  3. Howard Hughes Medical Institute, Salk Institute for Biological Studies, United States

Abstract

Two epigenetic pathways of transcriptional repression, DNA methylation and Polycomb repressive complex 2 (PRC2) are known to regulate neuronal development and function. However, their respective contributions to brain maturation are unknown. We found that conditional loss of the de novo DNA methyltransferase Dnmt3a in mouse excitatory neurons altered expression of synapse-related genes, stunted synapse maturation, and impaired working memory and social interest. At the genomic level, loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving adult neurons with an unmethylated, fetal-like epigenomic pattern at ~222,000 genomic regions. The PRC2-associated histone modification, H3K27me3, increased at many of these sites. Our data support a dynamic interaction between two fundamental modes of epigenetic repression during postnatal maturation of excitatory neurons, which together confer robustness on neuronal regulation.

Data availability

All sequencing data are available in the Gene Expression Omnibus under accession GSE141587. A genome browser displaying the sequencing data is available at https://brainome.ucsd.edu/annoj_private/mm_dnmt3a_ko/

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

Article and author information

Author details

  1. Junhao Li

    Department of Cognitive Science, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6784-3780
  2. Antonio Pinto-Duarte

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2215-7653
  3. Mark Zander

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8643-1407
  4. Michael S Cuoco

    Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Chi-Yu Lai

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Julia Osteen

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7058-3297
  7. Linjing Fang

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2232-2601
  8. Chongyuan Luo

    Genomic Analysis Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8541-0695
  9. Jacinta D Lucero

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Rosa Gomez-Castanon

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Joseph R Nery

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Isai Silva-Garcia

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Yan Pang

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Terrence J Sejnowski

    Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0622-7391
  15. Susan B Powell

    Department of Psychiatry, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Joseph R Ecker

    Plant Biology Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    ecker@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5799-5895
  17. Eran A Mukamel

    Department of Cognitive Science, University of California, San Diego, La Jolla, United States
    For correspondence
    emukamel@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3203-9535
  18. M Margarita Behrens

    Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    mbehrens@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7168-8186

Funding

National Institute of Mental Health (R01MH112763)

  • Joseph R Ecker
  • Eran A Mukamel
  • M Margarita Behrens

Kavli Foundation

  • Antonio Pinto-Duarte
  • Susan B Powell
  • M Margarita Behrens

Howard Hughes Medical Institute

  • Joseph R Ecker

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

Ethics

Animal experimentation: All animal procedures were conducted in accordance with the guidelines of the American Association for the Accreditation of Laboratory Animal Care and were approved by the Salk Institute for Biological Studies Institutional Animal Care and Use Committee (Protocol number 18-00006).

Reviewing Editor

  1. Anne E West, Duke University, United States

Version history

  1. Preprint posted: December 20, 2020 (view preprint)
  2. Received: January 28, 2021
  3. Accepted: May 22, 2022
  4. Accepted Manuscript published: May 23, 2022 (version 1)
  5. Version of Record published: June 6, 2022 (version 2)

Copyright

© 2022, Li 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. Junhao Li
  2. Antonio Pinto-Duarte
  3. Mark Zander
  4. Michael S Cuoco
  5. Chi-Yu Lai
  6. Julia Osteen
  7. Linjing Fang
  8. Chongyuan Luo
  9. Jacinta D Lucero
  10. Rosa Gomez-Castanon
  11. Joseph R Nery
  12. Isai Silva-Garcia
  13. Yan Pang
  14. Terrence J Sejnowski
  15. Susan B Powell
  16. Joseph R Ecker
  17. Eran A Mukamel
  18. M Margarita Behrens
(2022)
Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3
eLife 11:e66909.
https://doi.org/10.7554/eLife.66909

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