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

Titleknockout in excitatory neurons impairs postnatal synapse maturation and increases the repressive histone modification H3K27me3.
Publication TypeJournal Article
Year of Publication2022
AuthorsLi J, Pinto-Duarte A, Zander M, Cuoco MS, Lai C-Y, Osteen J, Fang L, Luo C, Lucero JD, Gomez-Castanon R, Nery JR, Silva-Garcia I, Pang Y, Sejnowski TJ, Powell SB, Ecker JR, Mukamel EA, M Behrens M
JournalElife
Volume11
Date Published2022 May 23
ISSN2050-084X
KeywordsAnimals, Brain, Disease Models, Animal, DNA Methyltransferase 3A, Histone Code, Histones, Mice, Mice, Knockout, Neurons, Polycomb Repressive Complex 2, Synapses
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 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 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.

DOI10.7554/eLife.66909
Alternate JournalElife
PubMed ID35604009
Grant ListR01MH112763 / MH / NIMH NIH HHS / United States
R01MH112763 / MH / NIMH NIH HHS / United States
Category: 
IRG Funded