PDF(Pubmed)
Abstract：
Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.
摘要：
静止（G0）的维持和退出对于哺乳动物的组织稳态和再生至关重要。这里,我们表明，甲基-CpG结合蛋白2（Mecp2）的表达是细胞周期依赖性的，并且在培养的细胞和损伤诱导的肝再生小鼠模型中负调节静止退出。具体来说,随着Mecp2缺失加速，Mecp2的急性减少是有效的静止退出所必需的，而Mecp2的过表达延迟了静止退出，Mecp2条件性敲除后强制表达Mecp2可挽救细胞周期重新进入。E3连接酶Nedd4介导Mecp2的泛素化和降解，从而促进静止退出。一项全基因组研究揭示了Mecp2在通过转录激活代谢基因同时抑制增殖相关基因来防止静止退出中的双重作用。特别是两个核受体的破坏，Rara或Nr1h3，加速静止出口，模仿Mecp2耗竭表型。我们的研究揭示了Mecp2作为静止退出和组织再生的重要调节剂的先前未被认可的作用。
