Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Nat Genet. 2012 Jan 22;44(3):343-7. doi: 10.1038/ng.1068.
Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown(1,2). The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive marks during development that persist into adulthood(3-9), 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 gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation. Deletion of Ezh2 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 gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.
成人疾病可能与宫内事件有关，但这种机制尚不清楚(1,2)。Polycomb 组蛋白甲基转移酶 Ezh2 通过在发育过程中沉积抑制性标记来稳定转录，这些标记在成年后仍然存在(3-9)，但其在出生后器官稳态中的功能尚不清楚。我们发现，Ezh2 通过抑制同源域转录因子基因 Six1 稳定心脏基因表达并预防心脏病变，Six1 基因在心脏祖细胞中起作用，但在心脏分化后稳定沉默。心脏祖细胞中 Ezh2 的缺失导致出生后心肌病变，并激活依赖于 Six1 的骨骼肌基因，导致心脏基因表达不稳定。Six1 诱导心肌细胞肥大和骨骼肌基因表达。此外，通过基因手段降低 Six1 水平可挽救 Ezh2 缺陷型心脏的病变。因此，Ezh2 在分化的心脏祖细胞中对 Six1 的抑制对于出生后心脏的稳定基因表达和稳态至关重要。我们的研究结果表明，胚胎祖细胞中的表观遗传失调是导致成人疾病和失调应激反应的一个易感因素。
