Differential brain ADRA2A and ADRA2C gene expression and epigenetic regulation in schizophrenia. Effect of antipsychotic drug treatment

Abstract

Postsynaptic α2A-adrenoceptor density is enhanced in the dorsolateral prefrontal cortex (DLPFC) of antipsychotic-treated schizophrenia subjects. This alteration might be due to transcriptional activation, and could be regulated by epigenetic mechanisms such as histone posttranslational modifications (PTMs). The aim of this study was to evaluate ADRA2A and ADRA2C gene expression (codifying for α2-adrenoceptor subtypes), and permissive and repressive histone PTMs at gene promoter regions in the DLPFC of subjects with schizophrenia and matched controls (n = 24 pairs). We studied the effect of antipsychotic (AP) treatment in AP-free (n = 12) and AP-treated (n = 12) subgroups of schizophrenia subjects and in rats acutely and chronically treated with typical and atypical antipsychotics. ADRA2A mRNA expression was selectively upregulated in AP-treated schizophrenia subjects (+93%) whereas ADRA2C mRNA expression was upregulated in all schizophrenia subjects (+53%) regardless of antipsychotic treatment. Acute and chronic clozapine treatment in rats did not alter brain cortex Adra2a mRNA expression but increased Adra2c mRNA expression. Both ADRA2A and ADRA2C promoter regions showed epigenetic modification by histone methylation and acetylation in human DLPFC. The upregulation of ADRA2A expression in AP-treated schizophrenia subjects might be related to observed bivalent chromatin at ADRA2A promoter region in schizophrenia (depicted by increased permissive H3K4me3 and repressive H3K27me3) and could be triggered by the enhanced H4K16ac at ADRA2A promoter. In conclusion, epigenetic predisposition differentially modulated ADRA2A and ADRA2C mRNA expression in DLPFC of schizophrenia subjects.

Integrating Transcriptomic and ChIP-Seq Reveals Important Regulatory Regions Modulating Gene Expression in Myometrium during Implantation in Pigs

“…We then examined the elements that may regulate the differential expression of the ADRA2A and some immune response genes identified in the study. A recent study on subjects with schizophrenia characterized that a promoter region in ADRA2A, epigenetically modified by both H3K4me3 and H3K27me3, could modulate the expression of ADRA2A in the dorsolateral prefrontal cortex [85]. Consistently, this study found that ADRA2A was highly expressed in the LM layer, and H3K4me3 was significantly enriched in its proximal promoter (≤1 kb).…”

Identification of potentially functional modules and diagnostic genes related to amyotrophic lateral sclerosis based on the WGCNA and LASSO algorithms

“…For example, there is a link between insulin resistance and cognitive impairment 58 . In this regard, the hub genes of FTD-related modules including HEPB2 59 , CAMK1G 60 , ADRA2G 61 , C22orf132 62 are associated with cognitive impairment. Increasing evidence points to closely relevant between insulin signaling impairment and pathologic mechanisms of cognitive dysfunction.…”

A novel preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs

“…A mouse knockout model showed increased startle reflex and aggression 27 . Differential gene expression 28 and genetic alterations 29 in ADRA2C also suggest a role in schizophrenia. DRD2 and DRD3 binding were associated with mammary and menstruation-related ADRs in SIDER 30–32 .…”