Mandla Ravi, Jung Catherine, Vedantham Vasanth
Division of Cardiology, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States.
Front Physiol. 2021 Jul 16;12:712666. doi: 10.3389/fphys.2021.712666. eCollection 2021.
Cardiac pacemaker cells differentiate and functionally specialize early in embryonic development through activation of critical gene regulatory networks. In general, cellular specification and differentiation require that combinations of cell type-specific transcriptional regulators activate expression of key effector genes by binding to DNA regulatory elements including enhancers and promoters. However, because genomic DNA is tightly packaged by histones that must be covalently modified in order to render DNA regulatory elements and promoters accessible for transcription, the process of development and differentiation is intimately connected to the epigenetic regulation of chromatin accessibility. Although the difficulty of obtaining sufficient quantities of pure populations of pacemaker cells has limited progress in this field, the advent of low-input genomic technologies has the potential to catalyze a rapid growth of knowledge in this important area. The goal of this review is to outline the key transcriptional networks that control pacemaker cell development, with particular attention to our emerging understanding of how chromatin accessibility is modified and regulated during pacemaker cell differentiation. In addition, we will discuss the relevance of these findings to adult sinus node function, sinus node diseases, and origins of genetic variation in heart rhythm. Lastly, we will outline the current challenges facing this field and promising directions for future investigation.
心脏起搏器细胞在胚胎发育早期通过关键基因调控网络的激活而发生分化并在功能上特化。一般来说，细胞特化和分化要求细胞类型特异性转录调节因子的组合通过与包括增强子和启动子在内的DNA调控元件结合来激活关键效应基因的表达。然而，由于基因组DNA被组蛋白紧密包装，而组蛋白必须进行共价修饰才能使DNA调控元件和启动子可用于转录，所以发育和分化过程与染色质可及性的表观遗传调控密切相关。尽管获取足够数量的纯起搏器细胞群体存在困难，限制了该领域的进展，但低投入基因组技术的出现有可能催化这一重要领域知识的快速增长。本综述的目的是概述控制起搏器细胞发育的关键转录网络，特别关注我们对起搏器细胞分化过程中染色质可及性如何被修饰和调控的新认识。此外，我们将讨论这些发现与成人窦房结功能、窦房结疾病以及心律遗传变异起源的相关性。最后，我们将概述该领域目前面临的挑战以及未来研究的有前景的方向。
