Halawa Sarah, Latif Najma, Tseng Yuan-Tsan, Ibrahim Ayman M, Chester Adrian H, Moustafa Ahmed, Aguib Yasmine, Yacoub Magdi H
Aswan Heart Centre, Aswan, Egypt.
Biotechnology Graduate Program, American University in Cairo, New Cairo, Egypt.
Front Cardiovasc Med. 2022 Apr 6;9:840647. doi: 10.3389/fcvm.2022.840647. eCollection 2022.
Cardiac valves exhibit highly complex structures and specialized functions that include dynamic interactions between cells, extracellular matrix (ECM) and their hemodynamic environment. Valvular gene expression is tightly regulated by a variety of mechanisms including epigenetic factors such as histone modifications, RNA-based mechanisms and DNA methylation. To date, methylation fingerprints of non-diseased human aortic and mitral valves have not been studied. In this work we analyzed the differential methylation profiles of 12 non-diseased aortic and mitral valve tissue samples (in matched pairs). Analysis of methylation data [reduced representation bisulfite sequencing (RRBS)] of 16,101 promoters genome-wide revealed 584 differentially methylated (DM) promoters, of which 13 were reported in endothelial mesenchymal trans-differentiation (EMT), 37 in aortic and mitral valve disease and 7 in ECM remodeling. Both functional classification as well as network analysis showed that the genes associated with the DM promoters were enriched for WNT-, Cadherin-, Endothelin-, PDGF-, HIF-1 and VEGF- signaling implicated in valvular physiology and pathophysiology. Additional enrichment was detected for TGFB-, NOTCH- and Integrin- signaling involved in EMT as well as ECM remodeling. This data provides the first insight into differential regulation of human aortic and mitral valve tissue and identifies candidate genes linked to DM promoters. Our work will improve the understanding of valve biology, valve tissue engineering approaches and contributes to the identification of relevant drug targets.
心脏瓣膜呈现出高度复杂的结构和特殊功能，包括细胞、细胞外基质（ECM）及其血流动力学环境之间的动态相互作用。瓣膜基因表达受到多种机制的严格调控，包括表观遗传因素，如组蛋白修饰、基于RNA的机制和DNA甲基化。迄今为止，尚未对非病变人类主动脉瓣和二尖瓣的甲基化指纹进行研究。在这项工作中，我们分析了12对非病变主动脉瓣和二尖瓣组织样本的差异甲基化谱。对全基因组16,101个启动子的甲基化数据[简化代表性亚硫酸氢盐测序（RRBS）]分析显示，有584个差异甲基化（DM）启动子，其中13个在内皮间充质转分化（EMT）中被报道，37个在主动脉瓣和二尖瓣疾病中被报道，7个在ECM重塑中被报道。功能分类以及网络分析均表明，与DM启动子相关的基因在参与瓣膜生理和病理生理的WNT、钙黏蛋白、内皮素、血小板衍生生长因子、低氧诱导因子-1和血管内皮生长因子信号通路中富集。还检测到参与EMT以及ECM重塑的转化生长因子-β、Notch和整合素信号通路有额外的富集。这些数据首次揭示了人类主动脉瓣和二尖瓣组织的差异调控，并鉴定了与DM启动子相关的候选基因。我们的工作将增进对瓣膜生物学、瓣膜组织工程方法的理解，并有助于确定相关的药物靶点。
