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

心肌细胞中应激诱导的启动子暂停释放程序可预防心肌梗死

基本信息

批准号：
10521252
负责人：
MICHAEL G ROSENFELD
金额：
$ 66.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521252
关键词：
3-Dimensional Acute Affinity Alleles Architecture Binding Binding Sites Biological CCCTC-binding factor Cardiac Cardiac Myocytes Cells Chromosomes DNA Data Deacetylase Disease Dissection Elements Enhancers Event Gene Expression Gene Expression Regulation Genes Genetic Carriers Genetic Transcription Genome Genomics Genotoxic Stress Homeostasis Human Genome Hydrogen Peroxide Hypoxia Individual Investigation Ischemia Licensing Link Liquid substance Mediating Modeling Modification Molecular Mus Myocardial Infarction Nucleic Acid Regulatory Sequences Organogenesis Oxidative Stress Phase Phosphorylation Physiological Positioning Attribute Property Proteins Reperfusion Injury Research Risk Role Signal Pathway Signal Transduction Sirtuins Site Stress Testing Tissues Transcriptional Regulation Zinc Fingers base biological adaptation to stress cardioprotection cell type cohort disorder risk epigenomics experimental study genome wide association study genome-wide in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes insight novel posttranscriptional programs promoter recruit response risk variant

项目摘要

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.

抽象的遗传毒性应激和转录程序改变的交集影响了许多疾病，疾病风险事件，但令人惊讶的是，在这方面很少知道，特别是关于风险等位基因心肌梗塞。根据我们的初始数据，我们可以确认 SIRT1启动子中的CTCF站点可以增加MI的风险。我们将研究以下假设基于诱导CTCF与缺氧或遗传毒性应激的功能重要性到SIRT1启动子中的同源站点，许可启动子暂停释放，导致急性刺激SIRT1转录。拟议的研究旨在揭示先前被忽视的基于临界染色体的重新分布的信号依赖性转录调节的策略在激活大型启动子暂停释放程序中，建筑蛋白-CTCF-具有重要的生物学后果，包括编码关键调节剂的基因-SIRT1。我们将研究以下假设应力引起的SIRT1转录和对氧化应激的反应的全球基因组计划在心肌细胞中，CTCF启动子募集介导，部分是由长距离相互作用的在心肌细胞中CTCF和LNCRNA的液体液相分离上，在MI风险等位基因中丢失载体。我们将研究IPSC衍生的，基因组序列中应力诱导的转录程序心肌细胞和测试假设通过评估小鼠引入风险等位基因的影响。和 IPSC的可用性带有SIRT1风险等位基因的因果关系，我们现在可以深入研究这些事件的确切机制，并评估存在很大的可能性心肌细胞暂停释放计划对于对急性侮辱的心脏反应很重要。这个想法染色体结构的关键仲裁者受关键结构蛋白的磷酸化调节，结合一组具有CTCF弱地点的启动子和许可的启动子，增加了基于转录的转录启动子暂停释放事件揭示了一种未欣赏的信号依赖性机制重要的生物学计划。