Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association

Falkenberg, Virginia R.; Gurbaxani, Brian M.; Unger, Elizabeth R.; Rajeevan, Mangalathu S.

doi:10.1007/s12017-010-8138-2

Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association

Journal Article · Wed Oct 13 00:00:00 EDT 2010 · NeuroMolecular Medicine

DOI:https://doi.org/10.1007/s12017-010-8138-2· OSTI ID:1816640

Falkenberg, Virginia R. ^[1]; Gurbaxani, Brian M. ^[2]; Unger, Elizabeth R. ^[2]; Rajeevan, Mangalathu S. ^[2]

Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States). Division of Viral and Rickettsial Diseases; OSTI
Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States). Division of Viral and Rickettsial Diseases

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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0014664

OSTI ID:: 1816640

Journal Information:: NeuroMolecular Medicine, Journal Name: NeuroMolecular Medicine Journal Issue: 1 Vol. 13; ISSN 1535-1084

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Chronic fatigue syndrome
Cortisol
DNA methylation
Gene expression
Polymorphism
Serotonergic neurotransmission
Serotonin receptor 2A (HTR2A)
Structural equation modeling

Functional Genomics of Serotonin Receptor 2A (HTR2A): Interaction of Polymorphism, Methylation, Expression and Disease Association

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References (33)

Cited By (18)

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