Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
Thromb Res. 2012 Mar;129(3):325-9. doi: 10.1016/j.thromres.2011.11.050. Epub 2011 Dec 20.
Proteomic and genomic technologies have recently defined almost the complete platelet transcriptome and proteome as well as many important protein-protein interactions that are critical for platelet function under normal and pathological conditions such as an abnormal platelet function and cardiovascular disease (CVD). In contrast, the study of epigenetic processes such as DNA methylation and histone modification is still an unexplored domain in this research. Epigenetic marks are erased in early embryogenesis and reset during development. Environmental influences can lead to stable changes in the epigenome that alter the individual's susceptibility to disease. We will focus on the progress of DNA methylation studies in CVD. Techniques for genomic-scale analysis of DNA methylation became available but at the current stage however, several questions are still open as methylation marks are tissue-specific and it is not yet known whether leukocyte DNA reflects the correct epigenetic signature. It also remains uncertain if the observed associations of epigenetic profiles with disease are causative or just epiphenomena. Preliminary evidence exists that changes in DNA methylation can alter platelet activity as shown for the imprinted GNAS cluster that codes for the stimulatory G protein alpha subunit (Gs). Gs interacts with adenylyl cyclase to generate cAMP, which is inhibitory for platelet function. Patients with abnormal GNAS methylation have platelet Gs hypofunction and can develop risk for thrombosis and ischemic stroke at young age. This review is a brief introduction to these different aspects in epigenomics with a focus on DNA methylation in CVD and platelet research.
蛋白质组学和基因组学技术最近已经定义了几乎完整的血小板转录组和蛋白质组，以及许多在正常和病理条件下（如血小板功能异常和心血管疾病（CVD））对血小板功能至关重要的重要蛋白质-蛋白质相互作用。相比之下，DNA 甲基化和组蛋白修饰等表观遗传过程的研究仍然是该研究中一个未探索的领域。表观遗传标记在早期胚胎发生中被擦除，并在发育过程中重新设置。环境影响会导致表观基因组发生稳定变化，从而改变个体对疾病的易感性。我们将重点介绍 CVD 中 DNA 甲基化研究的进展。用于基因组规模分析 DNA 甲基化的技术已经可用，但在当前阶段，仍然存在几个问题尚未解决，因为甲基化标记是组织特异性的，并且尚不清楚白细胞 DNA 是否反映了正确的表观遗传特征。也不确定观察到的表观遗传谱与疾病之间的关联是因果关系还是仅仅是表型。初步证据表明，DNA 甲基化的变化可以改变血小板的活性，正如编码刺激性 G 蛋白α亚基（Gs）的印迹 GNAS 簇所示。Gs 与腺苷酸环化酶相互作用生成 cAMP，cAMP 对血小板功能具有抑制作用。具有异常 GNAS 甲基化的患者血小板 Gs 功能低下，并且在年轻时可能会发生血栓形成和缺血性中风的风险。这篇综述简要介绍了表观基因组学的这些不同方面，重点介绍了 CVD 和血小板研究中的 DNA 甲基化。
