Dnmt3a knockout in excitatory neurons impairs postnatal synapse maturation and is partly compensated by repressive histone modification H3K27me3
Jacinta Dixie Lucero,
Joseph R. Nery,
Terrence J. Sejnowski,
Susan B Powell,
Joseph R. Ecker,
Eran A. Mukamel,
M. Margarita Behrens
Posted 20 Dec 2019
bioRxiv DOI: 10.1101/2019.12.20.883694
Posted 20 Dec 2019
Two epigenetic pathways of repression, DNA methylation and Polycomb repressive complex 2 (PRC2) mediated gene silencing, regulate neuron development and function, but their respective contributions 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. Loss of Dnmt3a abolished postnatal accumulation of CG and non-CG DNA methylation, leaving neurons with an unmethylated, fetal-like epigenomic pattern at ~140,000 genomic regions. The PRC2-associated histone modification H3K27me3 increased at many of these sites, partially compensating for the loss of DNA methylation. 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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