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H3K79me2 dynamics in medium spiny neurons mediate long-term behavioral and cell type-specific molecular effects of early life stress

ABSTRACT: Animals susceptible to chronic social defeat stress (CSDS) exhibit depression-related behaviors, and show aberrant transcription across several limbic brain regions. The nucleus accumbens (NAc) in particular shows unique susceptible versus resilient phenotypes at the transcriptional, neuroanatomical, and physiological levels. Early life stress (ELS) promotes susceptibility to CSDS in adulthood, but associated enduring changes in transcriptional control mechanisms in NAc have not yet been investigated. Here, we examined long-lasting changes in histone modifications induced in NAc by ELS and studied their underlying mechanisms in mediating heightened lifelong stress susceptibility in male and female mice. We identify methylation of lysine 79 of histone H3 (H3K79me) and the enzymes that control this modification, selectively in D2-type medium spiny neurons, as crucial for the expression of ELS-induced stress susceptibility, and reveal the transcriptional networks regulated by this mechanism. Finally, we demonstrate the potential clinical viability of this approach by showing that systemic delivery of a small molecule inhibitor of H3K79me reverses ELS-induced behavioral deficits.

ORGANISM(S): Mus musculus

PROVIDER: GSE133889 | GEO | 2020/12/09

REPOSITORIES: GEO

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Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

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H3K79me2 dynamics in medium spiny neurons mediate long-term behavioral and cell type-specific molecular effects of early life stress

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