Repressive Epigenetic Changes at themGlu2Promoter in Frontal Cortex of 5-HT_2AKnockout Mice

Abstract

Serotonin 5-HT 2A and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT 2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT 2A -KO mice. Disruption of 5-HT 2A receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor trimethylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT 2A receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT 2A -KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT 2A receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.

Acute Ethanol Alters Multiple Histone Modifications at Model Gene Promoters in the Cerebral Cortex

“…Antibodies were screened by assessing enrichment of the constitutively active gene, β-actin , over the neuronally repressed gene, ε-globin ; there was no difference in enrichment between EtOH and saline treated animals (Fig. S1) (Kurita et al, 2013). Antibodies were also validated by assessing binding to peptide arrays containing 46 histone modifications to the H3 N-terminal tail (Millipore #16-667); H3K27me3 and H3K4me3 antibodies bound to their stated histone modifications while the H3K9,14ac antibody bound H3K9ac but not H3K14ac (data not shown).…”

An Update on the Epigenetics of Psychotic Diseases and Autism

“…While HTR2A receptor mediated these effects (HT2RA null mutant mice exhibit no change), HDAC inhibitors could inhibit these GRM2 modifications as well as the effects of atypical antipsychotics in mice [121]. A disrupted HTR2A signaling may also lead to reduced activation of Egr1 (early growth response 1) promoter, and a decrease in H3 and H4 acetylation, and an increase in the level of H3K27 me3 at the promoter region of GRM2 suppressing its expression [122]. Meanwhile, the clozapine-induced chromatin modifications of GAD1 and RELN promoters can be augmented by HDAC inhibitors such as valproate, which are not dependent upon the status of catecholamine or serotonin receptors [123].…”

Maternal lipopolysaccharide treatment differentially affects 5-HT2A and mGlu2/3 receptor function in the adult male and female rat offspring

“…The mGlu2 receptors are G protein-coupled receptors that form covalently linked homodimers (Pin et al, 2003). Here, we measured mGlu2 IR as a monomer (Kurita et al, 2013) …”