沉默因子REST介导心脏肥大α-MHC反转调节的染色质重塑机制

心脏肥大是心力衰竭发生的关键环节，其中α-肌球蛋白重链（α-MHC）如何反转下调是一个重要的科学问题，涉及的机制尚未明了。我们前期发现，心肌细胞肥大时，阻遏物元件-1沉默子(REST)及招募的阻遏复合物分子水平上调，α-MHC表达下降；抑制REST则可下调阻遏复合物分子的水平，α-MHC反转上调，心脏肥大状况改善；并发现α-MHC基因序列具有潜在结合REST的阻遏物顺式元件。据此推测：受心脏重塑因素触发，REST通过顺式元件与α-MHC基因结合，并与Sin3A/CoREST互作聚集染色质重塑分子，招募的DNMT3a/b与IIaHDACs协同调节，压塑染色质而抑制α-MHC表达,导致心脏肥大。因此，本课题拟利用相关生物技术以及细胞和动物模型，全面解析心脏肥大时REST介导的特异表观分子在α-MHC调控域的反式占据及调节作用，阐明心脏肥大的表观机制，为揭示心衰病理生理过程提供新颖的科学依据。

Cardiac hypertrophy is a key link in the development of heart failure, in which the mechanism of α-MHC downregulation has not been fully understood so far. Our previous research found that the expression of REST and its recruitment epigenetic repressive complex was up-regulated with reduction of α-MHC expression during cardiac hypertrophy. Silencing REST notably inhibited the transcription of epigenetic repressive complex and attenuated the cardiac hypertrophy due to decrease of α-MHC expression. Furthermore, we found that the region of α-MHC gene harbored a cis-element sequences required for REST binding. Accordingly, it is speculated that triggered by cardiac remodeling factors, REST specifically binds to the α-MHC sequence, and interacts with Sin3A/CoREST to mediate the aggregation of chromatin remodeling complexes. The recruited DNMT3a/b and IIaHDACs synergistically remodel the chromatin of α-MHC into a condensed status that inhibits its expression, finally leading to cardiac hypertrophy. Therefore, this project intends to analyze the trans-occupation of REST-mediated chromatin remodeling complexes in the α-MHC sequence during cardiac hypertrophy, and explore the crucial epigenetic factors of the cardiac remodeling that is mediated through REST/α-MHC pathway based on genetic manipulation model, which might provide a new scientific evidence for revealing the pathophysiology of heart failure.