van Weerd Jan Hendrik, Christoffels Vincent M.
Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15 – L2-106, Amsterdam, 1105 AZ, The Netherlands
The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. The development of the CCS involves complex regulatory networks of transcription factors that act in stage, tissue and dose-dependent manners. As disrupted function or expression of these factors may lead to disorders in the development or function of components of the CCS associated with heart failure and sudden death, it is crucial to understand the molecular and cellular mechanisms underlying their complex regulation. Here, we discuss the regulation of genes driving CCS-specific gene expression and demonstrate the complexity of the mechanisms governing their regulatory networks. The three-dimensional conformation of chromatin has recently been recognized as an important regulatory layer, shaping the genome in regulatory domains and physically wiring gene promoters to their regulatory sequences. Knowledge of the mechanisms by which distal-acting regulatory sequences exert their function to drive tissue-specific gene expression and understanding how the three-dimensional chromatin landscape is involved in this regulation will increase our understanding of how disease-associated genomic variation affects the function of such sequences.
心脏传导系统（CCS）由独特的组件组成，这些组件启动并传导心脏腔室协调收缩所需的电冲动。CCS的发育涉及转录因子的复杂调控网络，这些转录因子以阶段、组织和剂量依赖的方式发挥作用。由于这些因子的功能或表达受到干扰可能会导致与心力衰竭和猝死相关的CCS组件发育或功能紊乱，因此了解其复杂调控背后的分子和细胞机制至关重要。在这里，我们讨论驱动CCS特异性基因表达的基因调控，并展示其调控网络机制的复杂性。染色质的三维构象最近被认为是一个重要的调控层面，它在调控域中塑造基因组，并将基因启动子与其调控序列物理连接起来。了解远端作用调控序列发挥功能以驱动组织特异性基因表达的机制，以及理解三维染色质景观如何参与这种调控，将增进我们对疾病相关基因组变异如何影响此类序列功能的理解。
