SWI/SNF Protein Component BAF250a Regulates Cardiac Progenitor Cell Differentiation by Modulating Chromatin Accessibility during Second Heart Field Development
SWI/SNF Protein Component BAF250a Regulates Cardiac Progenitor Cell Differentiation by Modulating Chromatin Accessibility during Second Heart Field Development
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DOI：
10.1074/jbc.m112.365080
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发表时间：
2012-07-13
影响因子：
4.8
通讯作者：
Wang, Zhong
中科院分区：
文献类型：
--
作者：
Lei, Ienglam;Gao, Xiaolin;Wang, Zhong
依赖于ATP的SWI/SNF染色质重塑复合体改变了染色质在特定位点的结构，促进了发育过程中组织特异性基因的调节。心脏生成需要几个SWI/SNF亚基。然而，SWI/SNF在心脏发生过程中介导心脏祖细胞分化的作用和机制还不是很清楚。我们对SWI/SNF染色质重塑复合体的研究发现，SWI/SNF的一个调节亚单位BAF250a在CPC分化中起着关键作用。BAF250a在小鼠第二心区(SHF)消融导致右室小梁缺陷、室间隔缺陷、永存动脉干、心肌增殖减少和胚胎死亡。利用胚胎干细胞培养系统模拟体内SHF CPC的形成和分化，我们已经证明了BAF250a在CPC中的消融特异性地抑制了心肌细胞的形成。此外，BAF250a选择性地调节心脏关键因子MEF2C、NKX2.5和Bmp10在SHF CPC中的表达。染色质免疫沉淀和DNase I消化分析表明，BAF250a通过选择性地与其靶基因启动子结合并招募SWI/SNF的催化亚基BRG1来调节染色质的可及性，从而调节基因的表达。因此，我们的结果确认BAF250a介导的染色质重塑是介导CPC分化的重要表观遗传学机制。
ATP-dependent SWI/SNF chromatin remodeling complexes alter the structure of chromatin at specific loci and facilitate tissue-specific gene regulation during development. Several SWI/SNF subunits are required for cardiogenesis. However, the function and mechanisms of SWI/SNF in mediating cardiac progenitor cell (CPC) differentiation during cardiogenesis are not well understood. Our studies of the SWI/SNF chromatin remodeling complex identified that BAF250a, a regulatory subunit of the SWI/SNF, plays a key role in CPC differentiation. BAF250a ablation in mouse second heart field (SHF) led to trabeculation defects in the right ventricle, ventricular septal defect, persistent truncus arteriosus, reduced myocardial proliferation, and embryonic lethality around E13. Using an embryonic stem cell culture system that models the formation and differentiation of SHF CPCs in vivo, we have shown that BAF250a ablation in CPCs specifically inhibits cardiomyocyte formation. Moreover, BAF250a selectively regulates the expression of key cardiac factors Mef2c, Nkx2.5, and Bmp10 in SHF CPCs. Chromatin immunoprecipitation and DNase I digestion assays indicate that BAF250a regulates gene expression by binding selectively to its target gene promoters and recruiting Brg1, the catalytic subunit of SWI/SNF, to modulate chromatin accessibility. Our results thus identify BAF250a-mediated chromatin remodeling as an essential epigenetic mechanism mediating CPC differentiation.