Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association
Virginia R. Falkenberg • Brian M. Gurbaxani • Elizabeth R. Unger • Mangalathu S. Rajeevan. September 2010. Neuromol Med : DOI 10.1007/s12017-010-8138-2
Abstract
Serotonergic neurotransmission plays a key role in the pathophysiology of neuropsychiatric illnesses. The functional significance of a promoter polymorphism, −1438G/A (rs6311), in one of the major genes of this system (serotonin receptor 2A, HTR2A) remains poorly understood in the context of epigenetic factors, transcription factors and endocrine influences.
We used functional and structural equation modeling (SEM) approaches to assess the contributions of the polymorphism (rs6311), DNA methylation and clinical variables to HTR2A expression in chronic fatigue syndrome (CFS) subjects from a population-based study.
HTR2A was up-regulated in CFS through allele-specific expression modulated by transcription factors at critical sites in its promoter: an E47 binding site at position −1,438, (created by the A-allele of rs6311 polymorphism), a glucocorticoid receptor (GR) binding site encompassing a CpG at position −1,420, and Sp1 binding at CpG methylation site −1,224.
Methylation at −1,420 was strongly correlated with methylation at −1,439, a CpG site that is dependent upon the G-allele of rs6311 at position −1,438. SEM revealed a strong negative interaction between E47 and GR binding (in conjunction with cortisol level) on HTR2A expression. This study suggests that the promoter polymorphism (rs6311) can affect both transcription factor binding and promoter methylation, and this along with an individual's stress response can impact the rate of HTR2A transcription in a genotype and methylation-dependent manner.
This study can serve as an example for deciphering the molecular determinants of transcriptional regulation of major genes of medical importance by integrating functional genomics and SEM approaches.
Confirmation in an independent study population is required.
The mission of MCS America (MCSA) is to propagate medical, legal, and social recognition for multiple chemical sensitivity (MCS) as a disorder of organic biological origin induced by toxic environmental insults; to provide support and referral services to the individuals with all illnesses of environmental origin; and to ensure that environmental toxicants are identified, reduced, regulated, and enforced through lobbying for effective legislation. © MCS America
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