Gene expression profile of right ventricles from adult wild type and Ezh2-deficient hearts

Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive marks during development that persist into adulthood, but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor Six1, which functions in cardiac progenitors but is stably silenced upon cardiac differentiation. Ezh2 deletion in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable postnatal heart gene expression and homeostasis. Our results suggest that epigenetic dysregulation in embryonic progenitor cells predisposes to adult disease and dysregulated stress responses. Four samples were analyzed. RNA was obtained from ventricles from two wild type and two Ezh2-deficient hearts.成年起病疾病可与宫内事件相关联，但其背后的机制仍不明晰。多梳蛋白组蛋白甲基转移酶（polycomb histone methyltransferase）Ezh2可通过在发育进程中沉积抑制性表观标记以稳定转录，此类标记可持续存在至成年阶段，但其在产后器官稳态中的功能尚不明确。本研究表明，Ezh2可通过沉默同源域转录因子（homeodomain transcription factor）Six1来稳定心脏基因表达并预防心脏病理发生——Six1在心脏祖细胞中发挥功能，但在心脏分化过程中会被稳定沉默。在心脏祖细胞中敲除Ezh2会引发产后心肌病理，并通过激活Six1依赖的骨骼肌基因破坏心脏基因表达的稳定性。Six1可诱导心肌细胞肥大及骨骼肌基因表达。此外，通过遗传学手段降低Six1的表达水平，可挽救Ezh2缺陷心脏的病理表型。因此，在分化的心脏祖细胞中，Ezh2介导的Six1沉默对于维持稳定的产后心脏基因表达及器官稳态至关重要。本研究结果提示，胚胎祖细胞的表观遗传失调会增加成年起病疾病及应激反应失调的易感性。本研究共分析4份样本，RNA提取自2份野生型心脏及2份Ezh2缺陷型心脏的心室组织。