Lewandowski Sara L, Janardhan Harish P, Smee Kevin M, Bachman Marcos, Sun Zheng, Lazar Mitchell A, Trivedi Chinmay M
Cardiovascular Medicine and Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cardiovascular Medicine and.
Hum Mol Genet. 2014 Jul 15;23(14):3801-9. doi: 10.1093/hmg/ddu093. Epub 2014 Feb 23.
Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme histone deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis.
先天性心脏缺陷通常源于心脏祖细胞的分化异常。尽管已经描述了参与心脏祖细胞分化的转录因子，但在此过程中相关的染色质修饰因子仍大多未知。在此，我们表明，在心脏祖细胞中缺乏染色质修饰酶组蛋白去乙酰化酶3（Hdac3）的小鼠胚胎表现出心肌细胞早熟分化、严重的心脏发育缺陷、Tbx5靶基因上调以及胚胎致死性。Hdac3与Tbx5发生物理相互作用并调节其乙酰化，以抑制Tbx5依赖的心肌细胞谱系特异性基因的激活。这些发现揭示了Hdac3在心脏祖细胞中对早期心脏发生起关键调节作用。
