Cancer Epigenetic and Biology Program, Institut d'Investigació Biomedica de Bellvitge, Hospital Duran i Reynals, Barcelona, Spain.
Epigenetics. 2011 Oct 1;6(10):1236-41. doi: 10.4161/epi.6.10.17654.
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.
在后基因组时代，一个基本的挑战是了解遗传变异如何影响表型变异性和疾病。最近的一些研究观察结果强调了一种机制，即常见的遗传多态性如何影响 DNA 甲基化，这是一种主要的表观遗传沉默机制。我们报告说，人类 TRPC3 基因的替代启动子受等位基因 DNA 甲基化调控，这由位于启动子 CpG 岛内的单个碱基对多态性 rs13121031 的基因型决定。常见的 G 等位基因与高水平的甲基化相关，而较少见的 C 等位基因是非甲基化的。这种甲基化模式在许多组织类型中都观察到，尽管 TRPC3 的表达仅限于大脑和心脏。TRPC3 在后脑中表达明显，杂合脑样本显示根据等位基因甲基化存在适度的偏倚，优先从 C 等位基因表达。TRPC3 基因编码一种瞬时受体电位通道，已被牵连小脑共济失调和心脏肥大。rs13121031 的基因型频率在共济失调患者和心脏肥大个体的队列中确定。这些分析显示，罕见的未甲基化纯合 C 基因型在特发性共济失调患者中出现的频率更高（Fisher 检验 p=0.06），但在具有已知突变的患者中（Fisher 检验 p=0.55）或在心脏病患者中（Fisher 检验 p=0.807）则不存在，与对照人群相比。我们的结果表明，TRPC3 替代启动子是一个甲基化数量性状位点，可能参与调节共济失调表型。
