Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.66909
Keywords
epigenetics; synapse; brain development; DNA methylation; Dnmt3a; H3K27me3; Mouse
Categories
Funding
- National Institute of Mental Health [R01MH112763]
- Kavli Foundation
- Howard Hughes Medical Institute
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Two epigenetic pathways, DNA methylation and PRC2, play important roles in neuronal development. This study found that loss of Dnmt3a affects synapse-related gene expression, impairs synapse maturation, and leads to working memory and social interest deficits. Genomic analysis revealed an unmethylated epigenomic pattern resembling fetal neurons in adult neurons upon loss of Dnmt3a.
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.
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