title: Genotype of an individual single nucleotide polymorphism regulates DNA methylation at the TRPC3 alternative promoter.
abstract: A fundamental challenge in the post-genomics era is to understand how genetic variants can influence phenotypic variability and disease. Recent observations from a number of studies have highlighted a mechanism by which common genetic polymorphisms can influence DNA methylation, a major epigenetic silencing mechanism. We report that the alternative promoter of the human TRPC3 gene is regulated by allelic DNA methylation, dictated by the genotype of a single base pair polymorphism, rs13121031 located within the promoter CpG island. The common G allele is associated with high levels of methylation, while the less prevalent C allele is unmethylated. This methylation profile is observed in many tissue types, despite the expression of TRPC3 being restricted to brain and heart. TRPC3 is prominently expressed in the hindbrain, and a heterozygous brain sample showed modest skewing according to the allelic methylation, with preferential expression from the C allele. The TRPC3 gene encodes a transient receptor potential channel that has been implicated in cerebellar ataxia and heart hypertrophy. The genotype-frequencies of rs13121031 were determined in cohorts of ataxia patients and in individuals with cardiac hypertrophy. These analyses revealed a statistical trend for the rare unmethylated homozygous C genotype to be present at a higher frequency in idiopathic ataxia patients (Fisher's test p=0.06), but not in those patients with known mutations (Fisher's test p=0.55) or in individuals with heart disease (Fisher's test p=0.807), when compared to a control population. Our results suggest that the TRPC3 alternative promoter is a methylation quantitative-trait locus that may be involved in modulating the ataxia phenotype.
authors.affiliation: Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Martin-Trujillo
authors.forename: Isabel
authors.initials: I
authors.lastname: Iglesias-Platas
authors.forename: Eliecer
authors.initials: E
authors.lastname: Coto
authors.forename: Marc
authors.initials: M
authors.lastname: Corral-Juan
authors.forename: Hector
authors.initials: H
authors.lastname: San Nicolás
authors.forename: Jordi
authors.initials: J
authors.lastname: Corral
authors.forename: Victor
authors.initials: V
authors.lastname: Volpini
authors.forename: Antoni
authors.initials: A
authors.lastname: Matilla-Dueñas
authors.forename: David
authors.initials: D
authors.lastname: Monk
mesh_terms: D002894:Chromosomes, Human, Pair 4; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D050052:TRPC Cation Channels / Q000235:genetics*
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel