A stress-induced promoter pause release program in cardiomyocytes protecting against myocardial infarction

摘要 遗传毒性应激和改变的转录程序的交叉影响许多疾病和 疾病风险事件，但令人惊讶的是，在这方面，特别是关于 心肌梗死的危险等位基因根据我们的初步数据，我们可以确认， SIRT 1启动子中的CTCF位点可增加MI的风险。我们将研究这是一个假设， 基于CTCF的诱导结合在响应缺氧或遗传毒性应激中的功能重要性， 与SIRT 1启动子中的同源位点连接，从而允许启动子暂停释放，导致急性免疫应答。 SIRT 1转录的刺激。这项研究旨在揭示一个以前被忽视的问题。 基于关键染色体重分布的信号依赖性转录调控策略 建筑蛋白- CTCF-在激活一个大的启动子暂停释放程序与重要的生物学 结果，包括基因编码的关键调节-SIRT 1。我们将研究一个假设， 应激诱导SIRT 1转录增加和氧化应激应答的全球基因组程序 在心肌细胞中，通过CTCF启动子募集介导，部分通过基于 心肌细胞中CTCF和lncRNA的液-液相分离，这在MI风险等位基因中丢失 载波我们将在iPSC衍生的基因组测序中研究应激诱导的转录程序， 心肌细胞，并通过评估在小鼠中引入风险等位基因的影响来检验假设。与 携带SIRT 1风险等位基因的致病SNP的iPSC的可用性，我们现在能够 深入研究这些事件的确切机制，并评估有很大的可能性， 心肌细胞暂停释放程序对于心脏对急性损伤的反应很重要。这个想法 染色体结构的关键仲裁者是由关键结构蛋白的磷酸化调节的， 结合到一组携带CTCF弱位点的启动子上， 启动子暂停释放事件揭示了一种不受重视的信号依赖性机制， 重要的生物学项目。

ABSTRACT The intersection of genotoxic stress and altered transcriptional programs impacts numerous disease and disease risk events, but surprisingly little is mechanistically known in this regard, particularly with respect to risk alleles for myocardial infarction. Based on our initial data, we can confirm that a single base alteration in a CTCF site in the SIRT1 promoter can increase the risk of MI. We will investigate the hypothesis that this is based on the functional importance of induced binding of CTCF to in response to hypoxia or genotoxic stress to the cognate site in the SIRT1 promoter, licensing a promoter pause release that results in an acute stimulation of SIRT1 transcription. The proposed research is directed at revealing a previously overlooked strategy for signal-dependent transcriptional regulation based on redistribution of the critical chromosomal architectural protein - CTCF- in activation of a large promoter pause release program with important biological consequences, including the gene encoding critical regulator - SIRT1. We will investigate the hypothesis that stress-induced increased transcription of SIRT1 and a global genomic program of response to oxidative stress in cardiomyocytes is mediated by CTCF promoter recruitment and, in part, by long distance interactions based on liquid-liquid phase separation of CTCF and lncRNAs in cardiomyocytes, which is lost in MI risk allele carriers. We will investigate the stress-induced transcriptional program in iPSC-derived, genome-sequenced cardiac myocytes and the test the hypothesis by assessing effects of introducing the risk allele in mice. With the availability of iPSCs harboring the causative SNP for the SIRT1 risk allele, we are now in a position to delve into the precise mechanism of these events, and assess the possibility that there is a large cardiomyocyte pause-release program important with respect to cardiac response to acute insults. The idea that a key arbiter of chromosome architecture is regulated by phosphorylation of a key architectural protein, binding to a set of promoters harboring weak sites for CTCF and licensing increased transcription based of promoter pause release events reveals an unappreciated signal-dependent mechanism for controlling important biological program.