Transcription factor ISL1 is essential for pacemaker development and function
Transcription factor ISL1 is essential for pacemaker development and function
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转录因子 ISL1 对于起搏器的发育和功能至关重要
DOI：
10.1172/jci68257
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发表时间：
2015-08-01
影响因子：
15.9
通讯作者：
Evans, Sylvia M.
中科院分区：
文献类型：
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作者：
Liang, Xingqun;Zhang, Qingquan;Evans, Sylvia M.
窦房结（SAN）维持有节奏的心跳;因此，更好地了解驱动SAN发育和功能的因素对于产生潜在的治疗方法至关重要，例如生物起搏器，用于窦性心律失常。在这里，我们确定了LIM同源域转录因子ISL 1在整个发育过程中对起搏细胞的存活、增殖和功能起着关键作用。对几种Isl 1突变小鼠品系（包括携带SAN特异性Isl 1缺失的动物）的分析表明，SAN内的Isl 1是早期胚胎存活的必要条件。对来自ISL 1缺陷SAN的FACS纯化细胞的RNA测序（RNA-seq）分析显示，许多对SAN功能至关重要的基因（包括编码转录因子和离子通道的基因）位于ISL 1的下游。染色质免疫沉淀分析进行抗ISL 1抗体和染色质提取物从FACS纯化的SAN细胞证明，ISL 1直接结合基因组区域内的几个基因所需的正常起搏器功能，包括亚基的L型钙通道，Ank 2和Tbx 3。与人类异常心律有关的其他基因也是ISL 1的直接靶点。总之，我们的研究结果表明，ISL 1调节大约三分之一的SAN特异性基因，表明ISL 1和其他SAN转录因子的组合可用于产生起搏细胞，并表明ISL 1突变可能是病窦综合征的基础。
The sinoatrial node (SAN) maintains a rhythmic heartbeat; therefore, a better understanding of factors that drive SAN development and function is crucial to generation of potential therapies, such as biological pacemakers, for sinus arrhythmias. Here, we determined that the LIM homeodomain transcription factor ISL1 plays a key role in survival, proliferation, and function of pacemaker cells throughout development. Analysis of several Isl1 mutant mouse lines, including animals harboring an SAN-specific Isl1 deletion, revealed that ISL1 within SAN is a requirement for early embryonic viability. RNA-sequencing (RNA-seq) analyses of FACS-purified cells from ISL1-deficient SANs revealed that a number of genes critical for SAN function, including those encoding transcription factors and ion channels, were downstream of ISL1. Chromatin immunoprecipitation assays performed with anti-ISL1 antibodies and chromatin extracts from FACS-purified SAN cells demonstrated that ISL1 directly binds genomic regions within several genes required for normal pacemaker function, including subunits of the L-type calcium channel, Ank2, and Tbx3. Other genes implicated in abnormal heart rhythm in humans were also direct ISL1 targets. Together, our results demonstrate that ISL1 regulates approximately one-third of SAN-specific genes, indicate that a combination of ISL1 and other SAN transcription factors could be utilized to generate pacemaker cells, and suggest ISL1 mutations may underlie sick sinus syndrome.