Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate
复制标题
Isl1 在心肌细胞命运的表观遗传控制中的开创性功能
DOI：
10.1038/s41422-019-0168-1
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发表时间：
2019-06-01
期刊：
影响因子：
44.1
通讯作者：
Dobreva, Gergana
中科院分区：
文献类型：
--
作者：
Gao, Rui;Liang, Xingqun;Dobreva, Gergana
从一个全能合子产生广泛不同的和专门的细胞类型涉及大规模的转录变化和染色质重组。先锋转录因子在编程表观基因组和促进在连续的细胞谱系特化和分化步骤期间募集额外的调节因子中发挥关键作用。在这里，我们表明，Isl 1作为一个先驱因素驱动心肌细胞谱系承诺，通过塑造心脏祖细胞的染色质景观。使用一个Isl 1亚型小鼠系，显示先天性心脏缺陷，全基因组分析的Isl 1结合在一起的RNA和ATAC测序的心脏祖细胞及其衍生物，我们发现了一个调控网络下游的Isl 1，协调心脏发生。从机制上讲，我们表明，Isl 1结合到致密的染色质，并与Brg 1-Baf 60 c为基础的SWI/SNF复合物协同工作，以促进允许的心脏谱系特异性改变的染色质景观不仅在心脏祖细胞中具有关键功能的基因，而且在Isl 1本身不再存在时高度表达的心肌细胞结构基因。因此，Isl 1/Brg 1-Baf 60 c复合物在协调适当的心脏发生和建立心肌细胞命运承诺的表观遗传记忆中起着至关重要的作用。
Generation of widely differing and specialized cell types from a single totipotent zygote involves large-scale transcriptional changes and chromatin reorganization. Pioneer transcription factors play key roles in programming the epigenome and facilitating recruitment of additional regulatory factors during successive cell lineage specification and differentiation steps. Here we show that Isl1 acts as a pioneer factor driving cardiomyocyte lineage commitment by shaping the chromatin landscape of cardiac progenitor cells. Using an Isl1 hypomorphic mouse line which shows congenital heart defects, genome-wide profiling of Isl1 binding together with RNA- and ATAC-sequencing of cardiac progenitor cells and their derivatives, we uncover a regulatory network downstream of Isl1 that orchestrates cardiogenesis. Mechanistically, we show that Isl1 binds to compacted chromatin and works in concert with the Brg1-Baf60c-based SWI/SNF complex to promote permissive cardiac lineage-specific alterations in the chromatin landscape not only of genes with critical functions in cardiac progenitor cells, but also of cardiomyocyte structural genes that are highly expressed when Isl1 itself is no longer present. Thus, the Isl1/Brg1-Baf60c complex plays a crucial role in orchestrating proper cardiogenesis and in establishing epigenetic memory of cardiomyocyte fate commitment.