Thienpont Bernard, Aronsen Jan Magnus, Robinson Emma Louise, Okkenhaug Hanneke, Loche Elena, Ferrini Arianna, Brien Patrick, Alkass Kanar, Tomasso Antonio, Agrawal Asmita, Bergmann Olaf, Sjaastad Ivar, Reik Wolf, Roderick Hywel Llewelyn
J Clin Invest. 2017 Jan 3;127(1):335-348. doi: 10.1172/JCI88353. Epub 2016 Nov 28.
Cardiac hypertrophic growth in response to pathological cues is associated with reexpression of fetal genes and decreased cardiac function and is often a precursor to heart failure. In contrast, physiologically induced hypertrophy is adaptive, resulting in improved cardiac function. The processes that selectively induce these hypertrophic states are poorly understood. Here, we have profiled 2 repressive epigenetic marks, H3K9me2 and H3K27me3, which are involved in stable cellular differentiation, specifically in cardiomyocytes from physiologically and pathologically hypertrophied rat hearts, and correlated these marks with their associated transcriptomes. This analysis revealed the pervasive loss of euchromatic H3K9me2 as a conserved feature of pathological hypertrophy that was associated with reexpression of fetal genes. In hypertrophy, H3K9me2 was reduced following a miR-217-mediated decrease in expression of the H3K9 dimethyltransferases EHMT1 and EHMT2 (EHMT1/2). miR-217-mediated, genetic, or pharmacological inactivation of EHMT1/2 was sufficient to promote pathological hypertrophy and fetal gene reexpression, while suppression of this pathway protected against pathological hypertrophy both in vitro and in mice. Thus, we have established a conserved mechanism involving a departure of the cardiomyocyte epigenome from its adult cellular identity to a reprogrammed state that is accompanied by reexpression of fetal genes and pathological hypertrophy. These results suggest that targeting miR-217 and EHMT1/2 to prevent H3K9 methylation loss is a viable therapeutic approach for the treatment of heart disease.
心脏对病理信号的肥厚性生长与胎儿基因的重新表达和心脏功能下降相关，并且常常是心力衰竭的先兆。相比之下，生理诱导的肥厚是适应性的，会导致心脏功能改善。选择性诱导这些肥厚状态的过程目前了解甚少。在此，我们分析了两种抑制性表观遗传标记H3K9me2和H3K27me3，它们参与稳定的细胞分化，特别是在生理和病理肥厚的大鼠心脏的心肌细胞中，并将这些标记与其相关的转录组进行关联。该分析揭示了常染色质H3K9me2的普遍缺失是病理肥厚的一个保守特征，这与胎儿基因的重新表达相关。在肥厚过程中，miR-217介导组蛋白H3K9二甲基转移酶EHMT1和EHMT2（EHMT1/2）表达降低后，H3K9me2减少。miR-217介导的、基因或药物介导的EHMT1/2失活足以促进病理肥厚和胎儿基因重新表达，而抑制该途径在体外和小鼠体内均能预防病理肥厚。因此，我们建立了一种保守机制，即心肌细胞表观基因组从其成熟细胞身份转变为重新编程状态，伴随胎儿基因重新表达和病理肥厚。这些结果表明，靶向miR-217和EHMT1/2以防止H3K9甲基化缺失是治疗心脏病的一种可行治疗方法。
