Cardiovascular Research Laboratory, Department of Medicine and Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
J Cell Biol. 2011 Aug 8;194(3):407-23. doi: 10.1083/jcb.201012049.
The mammalian heart loses its regenerative potential soon after birth. Adult cardiac myocytes (ACMs) permanently exit the cell cycle, and E2F-dependent genes are stably silenced, although the underlying mechanism is unclear. Heterochromatin, which silences genes in many biological contexts, accumulates with cardiac differentiation. H3K9me3, a histone methylation characteristic of heterochromatin, also increases in ACMs and at E2F-dependent promoters. We hypothesize that genes relevant for cardiac proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins. To test this hypothesis, we created cardiac-specific Rb and p130 inducible double knockout (IDKO) mice. IDKO ACMs showed a decrease in total heterochromatin, and cell cycle genes were derepressed, leading to proliferation of ACMs. Although Rb/p130 deficiency had no effect on total H3K9me3 levels, recruitment of HP1-γ to promoters was lost. Depleting HP1-γ up-regulated proliferation-promoting genes in ACMs. Thus, Rb and p130 have overlapping roles in maintaining the postmitotic state of ACMs through their interaction with HP1-γ to direct heterochromatin formation and silencing of proliferation-promoting genes.
哺乳动物的心脏在出生后不久就失去了再生能力。成年心肌细胞（ACMs）永久退出细胞周期，E2F 依赖性基因稳定沉默，尽管其潜在机制尚不清楚。异染色质在许多生物学背景下沉默基因，在心脏分化过程中积累。H3K9me3 是异染色质的一种组蛋白甲基化特征，在 ACMs 和 E2F 依赖性启动子中也增加。我们假设与心脏增殖相关的基因通过与 E2F 转录因子相互作用并招募异染色质蛋白 1（HP1）蛋白的视网膜母细胞瘤（Rb）家族成员靶向异染色质。为了验证这一假设，我们创建了心脏特异性 Rb 和 p130 诱导型双敲除（IDKO）小鼠。IDKO ACMs 总异染色质减少，细胞周期基因被去抑制，导致 ACMs 增殖。尽管 Rb/p130 缺失对总 H3K9me3 水平没有影响，但 HP1-γ 对启动子的募集丢失。耗尽 HP1-γ 可上调 ACMs 中促进增殖的基因。因此，Rb 和 p130 通过与 HP1-γ 相互作用，在维持 ACMs 的有丝后状态方面具有重叠作用，从而指导异染色质形成和增殖促进基因的沉默。
