Institute for Rare Diseases Research, Instituto de Salud Carlos III (ISCIII). Majadahonda, Madrid, Spain.
Gene Regulation in Cardiovascular Remodelling and Inflammation Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Nat Commun. 2024 Oct 4;15(1):8602. doi: 10.1038/s41467-024-52809-1.
Extensive genetic studies have elucidated cardiomyocyte differentiation and associated gene networks using single-cell RNA-seq, yet the intricate transcriptional mechanisms governing cardiac conduction system (CCS) development and working cardiomyocyte differentiation remain largely unexplored. Here we show that mice deleted for Dhx36 (encoding the Dhx36 helicase) in the embryonic or neonatal heart develop overt dilated cardiomyopathy, surface ECG alterations related to cardiac impulse propagation, and (in the embryonic heart) a lack of a ventricular conduction system (VCS). Heart snRNA-seq and snATAC-seq reveal the role of Dhx36 in CCS development and in the differentiation of working cardiomyocytes. Dhx36 deficiency directly influences cardiomyocyte gene networks by disrupting the resolution of promoter G-quadruplexes in key cardiac genes, impacting cardiomyocyte differentiation and CCS morphogenesis, and ultimately leading to dilated cardiomyopathy and atrioventricular block. These findings further identify crucial genes and pathways that regulate the development and function of the VCS/Purkinje fiber (PF) network.
广泛的遗传研究已经使用单细胞 RNA-seq 阐明了心肌细胞分化和相关基因网络，但控制心脏传导系统 (CCS) 发育和工作心肌细胞分化的复杂转录机制在很大程度上仍未被探索。在这里，我们展示了在胚胎或新生儿心脏中缺失 Dhx36（编码 Dhx36 解旋酶）的小鼠会出现明显的扩张型心肌病、与心脏冲动传播相关的体表心电图改变，以及（在胚胎心脏中）缺乏心室传导系统 (VCS)。心脏 snRNA-seq 和 snATAC-seq 揭示了 Dhx36 在 CCS 发育和工作心肌细胞分化中的作用。Dhx36 缺乏通过破坏关键心脏基因启动子 G-四联体的分辨率直接影响心肌细胞基因网络，影响心肌细胞分化和 CCS 形态发生，最终导致扩张型心肌病和房室传导阻滞。这些发现进一步确定了调节 VCS/浦肯野纤维 (PF) 网络发育和功能的关键基因和途径。
