Setdb1 Histone Methyltransferase Regulates Mood-Related Behaviors and Expression of the NMDA Receptor Subunit NR2B

Abstract

Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to Ͻ1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-␣-(4-hydroxyphenyl)-␤-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.

Epigenetics of the Depressed Brain: Role of Histone Acetylation and Methylation

“…Acute and subchronic (7 day) stress increased global levels of H3K9me3 in the DG and CA1 regions, whereas chronic (21 days) stress decreased the same mark in these regions, and the latter effect was reversed by antidepressant treatment. H3K9me3 is typically thought to be involved in heterochromatin formation and maintenance, but has recently been shown to be regulated by several types of chronic stimuli; for example, cocaine treatment (Maze et al, 2011), as well as being involved in regulating transcription of a very small subset of genes (Jiang et al, 2010). study suggests that H3K9me3 may have an adaptive role in stress models, a possibility supported by the antidepressant effects of overexpressing SETDB1 (a KMT that catalyzes H3K9me3) in broad forebrain regions (Jiang et al, 2010).…”

“…H3K9me3 is typically thought to be involved in heterochromatin formation and maintenance, but has recently been shown to be regulated by several types of chronic stimuli; for example, cocaine treatment (Maze et al, 2011), as well as being involved in regulating transcription of a very small subset of genes (Jiang et al, 2010). study suggests that H3K9me3 may have an adaptive role in stress models, a possibility supported by the antidepressant effects of overexpressing SETDB1 (a KMT that catalyzes H3K9me3) in broad forebrain regions (Jiang et al, 2010). Further work is needed to understand the underlying mechanisms involved, in particular, whether these adaptive effects of H3K9me3 are mediated by the repression of specific genes or, rather, of intergenic elements.…”

“…Further work is needed to understand the underlying mechanisms involved, in particular, whether these adaptive effects of H3K9me3 are mediated by the repression of specific genes or, rather, of intergenic elements. One possible gene target, directly implicated in antidepressant-like responses, is H3K9me3-mediated repression of grin2b, which encodes the NR2b subunit of NMDA receptors (Jiang et al, 2010).…”

Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development

“…It has been shown that ESET is expressed in ES cells and the postnatal brain (Ryu et al, 2006;Matsui et al, 2010;Jiang et al, 2010), but expression in the developing brain has not been examined extensively. We therefore performed in situ hybridization and immunohistochemical analyses with mouse embryos at different developmental stages.…”

Epigenetics in the Human Brain

“…Despite of the growing realization of the importance of these and other higher order chromatin structures for transcriptional regulation, very little is known about their role in the nervous system. Until recently, there were only three studies in the literature that explored loop formations in brain tissue (Dhar et al, 2009;Horike et al, 2005;Jiang et al, 2010), with a few additional papers using the brain as negative control for their studies on the sensory epithelium of the nose (Lomvardas et al, 2006) or the hematopoetic system (Simonis et al, 2006). However, to date, nothing is known about chromatin loopings in human brain.…”