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.
By contrast with the poorly regenerative mammalian heart, the laboratory model zebrafish can completely regenerate heart muscle after injury. In this proposal we will perform key studies to test the hypothesis that chromatin regulation underlies the regenerative capacity of the zebrafish heart. Gene regulation may be an aspect of heart regeneration in zebrafish that in the future will be amenable to control by small molecules - an attractive mechanism for regulating similar processes in humans.
| Goldman, Joseph Aaron; Kuzu, Guray; Lee, Nutishia et al. (2017) Resolving Heart Regeneration by Replacement Histone Profiling. Dev Cell 40:392-404.e5 |
| Kang, Junsu; Hu, Jianxin; Karra, Ravi et al. (2016) Modulation of tissue repair by regeneration enhancer elements. Nature 532:201-6 |
