Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Elife. 2024 May 15;12:RP89912. doi: 10.7554/eLife.89912.
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, or 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.
静止期（G0）的维持和退出对于哺乳动物组织的稳态和再生至关重要。在这里，我们表明，甲基化 CpG 结合蛋白 2（Mecp2）的表达与细胞周期相关，并负调控培养细胞和损伤诱导的肝再生小鼠模型中的静止期退出。具体而言，急性降低 Mecp2 的表达对于有效的静止期退出是必需的，因为 Mecp2 的缺失会加速静止期退出，而过表达 Mecp2 则会延迟静止期退出，并且在 Mecp2 条件性敲除后强制表达 Mecp2 可以挽救细胞周期的重新进入。E3 连接酶 Nedd4 介导 Mecp2 的泛素化和降解，从而促进静止期退出。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期退出的双重作用。特别是破坏两个核受体，即 或 ，可以加速静止期退出，模拟 Mecp2 耗竭表型。我们的研究揭示了 Mecp2 作为静止期退出和组织再生的重要调节因子的先前未被认识到的作用。
