Bioinformatics Analysis of 5HT2C Gene Cys23ser Polymorphism and Epigenetics Insights into the HTR2C Receptor Gene Regulation: Implications for Physiological Roles in the Brain
Kiran Kumar Halagur Bhogegowda *
Former Post-doc NCBS, Bangalore. Wilson Garden, Bangalore-560030, affiliated to Nrupathunga University, Bengaluru, 560001, India.
Sajeeda Niketh
Department of Biochemistry, Nrupathunga University, Bengaluru, 560001, India.
Sowmyashree BS
Department of Biotechnology, Nrupathunga University, Bengaluru, 560001, India.
Tenkanidiyooru Ramamoorthy Prashith Kekuda
Department of Microbiology, S.R.N.M College of Applied Science. N.E.S Campus. Balraj urs Road, Shimoga-577201, India.
*Author to whom correspondence should be addressed.
Abstract
The expression profile, signaling and neuronal functions of the 5-HT2C receptor makes it a candidate of interest for the treatment of several neuropsychiatric diseases. The encoded ligand-gated G-protein coupled receptor (GPCR) protein responds to cell signaling through several neurotransmitters. Signal transduction through G-proteins is a prominent feature of several eukaryotes. In this review and analysis paper, we provide background literature on the unique biochemical, structural, and pharmacological properties of the 5-HT2c receptor and gene architecture, regulation, RNA editing and association studies of polymorphisms.Also on the evolutionary, and phylogenetic paths. of the 5HT2C gene. We conduct in silico predictions using bioinformatics tools SIFT and POLYPHEN to assess the effect of Cys23ser substitution in the N-terminal extracellular loop. Further, epigenetic analysis of the promoter and regions flanking the exon such as (DNase I Hypersensitivity, enhancer with TF binding site); methylation analysis of promoter (CpG methylation and CpG island); and histone marks with FAIRE. The results suggested that the cys23ser substitution can affect the 3D-protein structure. The additional cysteine amino acids (position-23,235,341) in human receptor could enable additional structural stability to the protein and may have evolved from previous ancestors (various mammals and primates) to aid the modulation of behavioral traits under evolutionary pressure. The alterations in DNA methylation and associated regulatory elements in promoter and upstream could impact gene expression, inactivation, genome stabilization, and inheritance which could have relevance in pathological states in the Central nervous system (CNS).
Keywords: GPCR protein, RNA editing, Cys23ser variant, methylation, FAIRE