CHROMATIN REGULATORY EVENTS UNDERLYING HEART REGENERATION

心脏再生背后的染色质调控事件

• 批准号: 8592837
• 负责人: Joseph A. Goldman
• 金额: $ 5.39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592837
• 关键词: Address; Adult; Affinity; Animal Model; Cardiac; Cardiac Myocytes; Chromatin; Chromatin Structure; Chromatin Structure Alteration; Cicatrix; DNA Sequence Rearrangement; Data; Developmental Gene; Embryo; Embryonic Heart; Event; Excision; Future; Gene Expression Regulation; Genes; Genome; Goals; Heart; Heart Ventricle; Heterochromatin; Histone H3.3; Human; Image; Injury; Institutes; Laboratories; Mammals; Microscopy; Modeling; Myocardial Infarction; Myocardium; Natural regeneration; Nucleosomes; Organism; Phenotype; Process; Production; Reagent; Recovery; Regulation; Regulator Genes; Sampling; Signal Pathway; Site; Staging; Structure; Testing; Tissues; Transgenic Organisms; Zebrafish; cardiogenesis; cell type; injured; insight; programs; public health relevance; regenerative; research study; response; small molecule

DESCRIPTION (provided by applicant): Zebrafish have a remarkable capacity to regenerate new heart muscle after major cardiac damage. Therefore, they represent an important model organism to discover mechanisms for cardiomyocyte recovery after myocardial infarction. In zebrafish, regeneration proceeds by dedifferentiation and subsequent proliferation of mature cardiomyocytes. Although some factors important for embryonic heart development are re-expressed during heart regeneration, it is unclear how dedifferentiation is achieved and how embryonic programs are reactivated. Chromatin organization is a principal mechanism to institute changes in differentiation, but whether chromatin structure changes to facilitate heart regeneration has not been examined. In preliminary studies, I have observed widespread rearrangement of chromatin structure in cardiac tissue in the first day after massive injury to the cardiac ventricle. Additional preliminary data suggest that nucleosome turnover may be a feature of these early large-scale changes during regeneration. The goal of this proposal is to explore how changes in nucleosome organization underlie key regulatory events during heart regeneration. Primarily, I will use nucleosome turnover as a marker to uncover regions of the genome undergoing rearrangement. 1) I will examine changes in nucleosome turnover and heterochromatin structure during early regeneration stages, when cardiomyocytes initiate dedifferentiation. 2) I will uncover gene regulatory loci activated specifically during regeneratio. Active genes and their regulatory domains are regions of rapid nucleosome turnover. Therefore, regions of nucleosome turnover can point to gene programs necessary for the production of new cardiomyocytes. Using nucleosome turnover, I will test the hypothesis that regeneration-specific alterations of chromatin structure underlie changes in cardiomyocyte differentiation during zebrafish heart regeneration. Ultimately, these findings will help identify processes and signaling pathways that may be exploited to promote recovery of cardiomyocytes in less regenerative organisms like mammals.

描述（由申请人提供）：斑马鱼具有在严重心脏损伤后再生新心肌的显著能力。因此，它们代表了发现心肌梗死后心肌细胞恢复机制的重要模式生物。在斑马鱼中，再生通过成熟心肌细胞的去分化和随后的增殖进行。虽然一些对胚胎心脏发育很重要的因子在心脏再生过程中重新表达，但目前还不清楚去分化是如何实现的，以及胚胎程序是如何重新激活的。染色质组织是一个主要的机制，研究变化的分化，但是否染色质结构的变化，以促进心脏再生尚未检查。在初步的研究中，我观察到大面积心肌损伤后的第一天，心脏组织中广泛的染色质结构重排， 心室额外的初步数据表明，核小体营业额可能是再生过程中这些早期大规模变化的一个特点。本提案的目标是探索核小体组织的变化如何成为心脏再生过程中关键调控事件的基础。首先，我将使用核小体转换作为标记，以揭示基因组中正在发生重排的区域。1)我将研究在心肌细胞开始去分化的早期再生阶段，核小体周转和异染色质结构的变化。2)我将揭示在再生过程中被激活的基因调控位点。活性基因及其调控域是核小体快速更新的区域。因此，核小体周转区域可以指向产生新心肌细胞所必需的基因程序。使用核小体营业额，我将测试这一假设，即在斑马鱼心脏再生过程中，心肌细胞分化的变化是染色质结构再生特异性改变的基础。最终，这些发现将有助于确定可能用于促进哺乳动物等再生性较低的生物体中心肌细胞恢复的过程和信号通路。