The recent identification of cardiac progenitor cells (CPCs) provides a new paradigm for studying and treating heart disease. To realize the full potential of CPCs for therapeutic purposes, it is essential to understand the genetic and epigenetic mechanisms guiding CPC differentiation into cardiomyocytes, smooth muscle, or endothelial cells. At present, our rudimentary knowledge about the epigenetic regulation of lineage differentiation presents a considerable roadblock to developing cell-based therapies. ATP-dependent chromatin remodelers mediate one critical epigenetic mechanism. These large multiprotein complexes open up chromatin to modulate transcription factor access to DNA. SWI/SNF, one of the major types of chromatin remodelers, plays a key role in various aspects of development, including heart development and disease. To decipher SWI/SNF-mediated epigenetic mechanisms in CPC differentiation, we have focused on a key regulatory subunit BAF250a that mediates SWI/SNF assembly/recruitment and controls nucleosome density as well as histone methylation and ubiquitylation. While the SWI/SNF complex and BAF250a are expressed in multiple tissues besides heart, the SWI/SNF complex is uniquely deployed in each tissue to propel tissue-specific differentiation programs. Thus, understanding how a general factor, BAF250a, is utilized to drive the cardiogenic program will instruct us about the steps necessary to direct a multipotent cell into the cardiomyocyte lineage. Indeed, our extensive preliminary data show that BAF250a deletion in second heart field (SHF) caused non-trabeculated right ventricle and ventricular septal defects and embryonic lethality around E13. We have established ESC-based in vitro systems that recapitulate the formation and differentiation of SHF CPCs in vivo and showed that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. BAF250a ablation in CPCs also selectively down-regulated the expression of key cardiac transcription factors Mef2c and Nkx2.5 but not Isl1 and Gata4. Thus, we hypothesize that BAF250a-mediated chromatin modifications enable the proper expression of a subset of transcription factors essential for CPC differentiation into cardiomyocytes. Therefore, we propose to determine the function of BAF250a in regulating SHF CPC differentiation (Aim 1), to test the hypothesis that BAF250a is essential for the assembly and recruitment of cSWI/SNF complex to its targets (Aim 2) and to test the hypothesis that BAF250a-mediated epigenetic modifications control CPC differentiation by regulating the promoter accessibility of key cardiac transcription factors (Aim 3). These studies will generate novel insights into epigenetic mechanisms that govern CPC differentiation and may have significant implications in understanding and treating heart disease.
Accomplishing these studies will generate novel insights into epigenetic mechanisms that govern cardiac progenitor cell differentiation. These studies will help identify chromatin marks and transcription and epigenetic factors that can promote specification, self-renewal and differentiation of cardiac progenitor cells and provide candidate targets to improve cardiac stem cell-based therapies.
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