CHROMATIN REGULATORY EVENTS UNDERLYING HEART REGENERATION

描述（由申请人提供）：斑马鱼在心脏严重损伤后具有显著的再生新心肌的能力。因此，它们是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，再生通过去分化和随后的成熟心肌细胞增殖进行。虽然一些对胚胎心脏发育重要的因素在心脏再生过程中重新表达，但目前尚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。染色质组织是导致分化变化的主要机制，但染色质结构变化是否促进心脏再生尚未得到研究。在初步研究中，我观察到，在心脏受到严重损伤后的第一天，心脏组织中染色质结构普遍重排

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.