Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes.
Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes.
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DOI：
10.1083/jcb.201012049
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发表时间：
2011-08-08
期刊：
影响因子：
--
通讯作者：
Maclellan WR
中科院分区：
文献类型：
--
作者：
Sdek P;Zhao P;Wang Y;Huang CJ;Ko CY;Butler PC;Weiss JN;Maclellan WR
Rb和p130都是募集介导成年心肌细胞增殖基因沉默的异染色质蛋白所必需的。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）永久性地退出细胞周期，e2f依赖性基因稳定地沉默，尽管潜在的机制尚不清楚。异染色质，在许多生物学环境中沉默基因，随着心脏分化而积累。H3K9me3，异染色质的组蛋白甲基化特征，也在ACMs和e2f依赖性启动子中增加。我们假设视网膜母细胞瘤（Rb）家族成员与E2F转录因子相互作用并募集异染色质蛋白1 （HP1）蛋白，从而将心脏增殖相关基因靶向异染色质。为了验证这一假设，我们创建了心脏特异性Rb和p130诱导双敲除（IDKO）小鼠。IDKO ACMs显示总异染色质减少，细胞周期基因被抑制，导致ACMs增殖。虽然Rb/p130缺乏对H3K9me3总水平没有影响，但HP1-γ向启动子的募集丢失。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的相互作用来指导异染色质的形成和增殖促进基因的沉默，在维持ACMs有丝分裂后状态方面具有重叠的作用。
Both Rb and p130 are required for the recruitment of heterochromatin proteins that mediate silencing of proliferation genes in adult cardiac myocytes. 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.
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影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
10.5
作者：
Cammas, F;Herzog, M;Losson, R
通讯作者：
Losson, R
影响因子：
5.3
作者：
Chen, TT;Wang, JYJ
通讯作者：
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视网膜母细胞瘤抑制组蛋白H3赖氨酸27的蛋白质依赖性甲基化与不可逆的细胞周期出口有关。
影响因子：
7.8
作者：
Blais, Alexandre;van Oevelen, Chris J. C.;Margueron, Raphael;Acosta-Alvear, Diego;Dynlacht, Brian David
通讯作者：
Dynlacht, Brian David
影响因子：
5.3
作者：
JAMES, TC;ELGIN, SCR
通讯作者：
ELGIN, SCR