| Literature DB >> 33723435 |
Hope Kronman1, Angélica Torres-Berrío1, Simone Sidoli2,3, Orna Issler1, Arthur Godino1, Aarthi Ramakrishnan1, Philipp Mews1, Casey K Lardner1,4, Eric M Parise1, Deena M Walker1,5, Yentl Y van der Zee1, Caleb J Browne1, Brittany F Boyce1, Rachael Neve6, Benjamin A Garcia2, Li Shen1, Catherine J Peña7,8, Eric J Nestler9.
Abstract
Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, with aberrant transcription across several limbic brain regions, most notably in the nucleus accumbens (NAc). Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in the NAc have not yet been investigated. In this study, we examined long-lasting changes to histone modifications in the NAc of male and female mice exposed to ELS. Dimethylation of lysine 79 of histone H3 (H3K79me2) and the enzymes (DOT1L and KDM2B) that control this modification are enriched in D2-type medium spiny neurons and are shown to be crucial for the expression of ELS-induced stress susceptibility. We mapped the site-specific regulation of this histone mark genome wide to reveal the transcriptional networks it modulates. Finally, systemic delivery of a small molecule inhibitor of DOT1L reversed ELS-induced behavioral deficits, indicating the clinical relevance of this epigenetic mechanism.Entities:
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Year: 2021 PMID： 33723435 PMCID： PMC8216773 DOI： 10.1038/s41593-021-00814-8
Source DB: PubMed Journal: Nat Neurosci ISSN： 1097-6256 Impact factor: 28.771