Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3
- University of California, San Diego, United States
- Salk Institute for Biological Studies, United States
- 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/
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Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouseNCBI Gene Expression Omnibus, GSE141587.
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Global epigenomic reconfiguration during mammalian brain developmentNCBI Gene Expression Omnibus, GSE47966.
Article and author information
Author details
Antonio Pinto-Duarte
Terrence J Sejnowski
M Margarita Behrens
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.
Reviewing Editor
- Anne E West, Duke University, United States
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).
Version history
- Preprint posted: December 20, 2020 (view preprint)
- Received: January 28, 2021
- Accepted: May 22, 2022
- Accepted Manuscript published: May 23, 2022 (version 1)
- 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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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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