Cell-Type-Specific Epigenetic Editing at the Fosb Gene Controls Susceptibility to Social Defeat Stress

Abstract

Chronic social defeat stress regulates the expression of Fosb in the nucleus accumbens (NAc) to promote the cell-type-specific accumulation of ΔFosB in the two medium spiny neuron (MSN) subtypes in this region. ΔFosB is selectively induced in D1-MSNs in the NAc of resilient mice, and in D2-MSNs of susceptible mice. However, little is known about the consequences of such selective induction, particularly in D2-MSNs. This study examined how cell-type-specific control of the endogenous Fosb gene in NAc regulates susceptibility to social defeat stress. Histone post-translational modifications (HPTMs) were targeted specifically to Fosb using engineered zinc-finger proteins (ZFPs). Fosb-ZFPs were fused to either the transcriptional repressor, G9a, which promotes histone methylation or the transcriptional activator, p65, which promotes histone acetylation. These ZFPs were expressed in D1- vs D2-MSNs using Cre-dependent viral expression in the NAc of mice transgenic for Cre recombinase in these MSN subtypes. We found that stress susceptibility is oppositely regulated by the specific cell type and HPTM targeted. We report that Fosb-targeted histone acetylation in D2-MSNs or histone methylation in D1-MSNs promotes a stress-susceptible, depressive-like phenotype, while histone methylation in D2-MSNs or histone acetylation in D1-MSNs increases resilience to social stress as quantified by social interaction behavior and sucrose preference. This work presents the first demonstration of cell- and gene-specific targeting of histone modifications, which model naturally occurring transcriptional phenomena that control social defeat stress behavior. This epigenetic-editing approach, which recapitulates physiological changes in gene expression, reveals clear differences in the social defeat phenotype induced by Fosb gene manipulation in MSN subtypes.

Chromatin-mediated alternative splicing regulates cocaine reward behavior

“…Persistence of cocaine-driven changes in isoform expression may underlie the chronic nature of addiction, analogous to permanent alternative isoform expression during cell-fate determination (Schwartzentruber et al, 2018;Xu et al, 2017). It is well established that cocaine epigenetically regulates gene expression Cates et al, 2018;Damez-Werno et al, 2012Feng et al, 2014;Hamilton et al, 2017;Heller et al, 2014Heller et al, , 2016Maze et al, 2011;Taniguchi et al, 2012), yet mechanism(s) by which cocaine-induced epigenetic modifications regulate alternative splicing is largely unexplored. Prior data indicate that a subset alternatively spliced genes after investigator-administered cocaine are enriched in the splice factor motif for A2BP1(Rbfox1/Fox-1), as well as the hPTM, H3K4me3 (Feng et al, 2014).…”

Multi-OMIC analysis of brain and serum from chronically-stressed mice reveals network disruptions in purine metabolism, fatty acid beta-oxidation, and antioxidant activity that are reversed by antidepressant treatment

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“…Samples were diluted 50 times in isopropanol:methanol:acetonitrile:water (3:3:3:1, by volume) with 2 mM ammonium acetate in order to optimize ionization efficiency in positive and negative modes. Electrospray ionization-MS was performed on a TripleTOF® 5600 + (SCIEX, Framingham, MA), coupled to a customized direct injection loop on an Ekspert microLC200 system (SCIEX) as described 7 . Lipid species with >50% missing values were removed, with remaining missing values estimated (the half of the minimum positive values in the original data assumed to be the detection limit) and IQR filtered, normalized to the median, glog transformed, and autoscaled.…”

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“…1) (Maze et al, , 2014. Furthermore, these epigenetic changes at individual gene loci have been demonstrated to be functionally relevant for both drug-and stress-related behaviors (Heller et al, 2014(Heller et al, , 2016Hamilton et al, 2018).…”