Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, Netherlands.
Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands.
Nat Commun. 2023 Aug 5;14(1):4716. doi: 10.1038/s41467-023-40203-2.
The inability of adult human cardiomyocytes to proliferate is an obstacle to efficient cardiac regeneration after injury. Understanding the mechanisms that drive postnatal cardiomyocytes to switch to a non-regenerative state is therefore of great significance. Here we show that Arid1a, a subunit of the switching defective/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex, suppresses postnatal cardiomyocyte proliferation while enhancing maturation. Genome-wide transcriptome and epigenome analyses revealed that Arid1a is required for the activation of a cardiomyocyte maturation gene program by promoting DNA access to transcription factors that drive cardiomyocyte maturation. Furthermore, we show that ARID1A directly binds and inhibits the proliferation-promoting transcriptional coactivators YAP and TAZ, indicating ARID1A sequesters YAP/TAZ from their DNA-binding partner TEAD. In ischemic heart disease, Arid1a expression is enhanced in cardiomyocytes of the border zone region. Inactivation of Arid1a after ischemic injury enhanced proliferation of border zone cardiomyocytes. Our study illuminates the pivotal role of Arid1a in cardiomyocyte maturation, and uncovers Arid1a as a crucial suppressor of cardiomyocyte proliferation.
成年人心肌细胞不能增殖是损伤后有效心脏再生的障碍。因此，了解驱动出生后心肌细胞转变为非再生状态的机制具有重要意义。在这里，我们表明 Arid1a，一个转换缺陷/蔗糖非发酵（SWI/SNF）染色质重塑复合物的亚基，抑制出生后心肌细胞的增殖，同时增强成熟。全基因组转录组和表观基因组分析表明，Arid1a 通过促进与驱动心肌细胞成熟的转录因子的 DNA 接触，激活心肌细胞成熟基因程序。此外，我们表明 ARID1A 直接结合并抑制促进增殖的转录共激活因子 YAP 和 TAZ，表明 ARID1A 将 YAP/TAZ 从其 DNA 结合伴侣 TEAD 上隔离。在缺血性心脏病中，Arid1a 在边缘区心肌细胞中的表达增强。缺血损伤后 Arid1a 的失活增强了边缘区心肌细胞的增殖。我们的研究阐明了 Arid1a 在心肌细胞成熟中的关键作用，并揭示了 Arid1a 作为心肌细胞增殖的关键抑制因子。
