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Start Over Author "Lardner CK" Journal nature neuroscience
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2. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons.

Author

Kronman H, Torres-Berrío A, Sidoli S, Issler O, Godino A, Ramakrishnan A, Mews P, Lardner CK, Parise EM, Walker DM, van der Zee YY, Browne CJ, Boyce BF, Neve R, Garcia BA, Shen L, Peña CJ, and Nestler EJ

Subjects
Animals, F-Box Proteins metabolism, Gene Expression Regulation, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Male, Mice, Histone Demethylases metabolism, Neurons metabolism, Nucleus Accumbens metabolism, Receptors, Dopamine D1 metabolism, Receptors, Dopamine D2 metabolism, Stress, Psychological metabolism
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.

Published
2021
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