Department of Medicine and Division of Cardiovascular Medicine and.
Hum Mol Genet. 2013 Dec 20;22(25):5107-20. doi: 10.1093/hmg/ddt365. Epub 2013 Aug 2.
Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.
平滑肌细胞（SMC）增殖是血管损伤和疾病的标志。在培养中的 SMC 增殖和体内新生内膜形成过程中会发生全局低甲基化。无论低甲基化是程序性还是随机发生的，识别这些变化对于理解血管疾病都很重要，因为维持细胞的表观遗传特征对于维持细胞表型至关重要。在传代过程中，培养中的增殖主动脉 SMC 出现全基因组低甲基化，同时 DNMT1 表达降低。通过对基因组进行全基因组筛选，发现了在增殖过程中发生低甲基化的基因组区域，并且通过“基因组收敛”选择了一个包含胶原，XV 型，α 1（COL15A1）的区域进行特征描述。COL15A1 转录本和蛋白水平随着与 DNA 甲基化相关的转录本依赖性降低而增加，并且该转录本对 5-Aza-2'-脱氧胞苷的处理敏感，提示 DNA 甲基化介导的基因表达。表型上，COL15A1 的敲低增加了 SMC 的迁移并减少了增殖，COL15A1 的表达在动脉粥样硬化病变中被诱导，并定位于动脉粥样硬化帽。COL15A1 中的一个与动脉粥样硬化显著相关的序列变异（rs4142986，P=0.017，OR=1.434）发生甲基化，风险等位基因的甲基化与基因表达降低和人类主动脉粥样硬化增加相关。总之，COL15A1 在 SMC 增殖过程中发生低甲基化，随之而来的基因表达增加可能会影响 SMC 表型和动脉粥样硬化形成。低甲基化基因，如 COL15A1，为同时发生的表观遗传调控和遗传易感性提供了证据，并定义了一类因果靶标，它们位于遗传和表观遗传倾向在复杂疾病病因学中的交叉点。
