eLife (May 2024)

Mecp2 fine-tunes quiescence exit by targeting nuclear receptors

  • Jun Yang,
  • Shitian Zou,
  • Zeyou Qiu,
  • Mingqiang Lai,
  • Qing Long,
  • Huan Chen,
  • Ping lin Lai,
  • Sheng Zhang,
  • Zhi Rao,
  • Xiaoling Xie,
  • Yan Gong,
  • Anling Liu,
  • Mangmang Li,
  • Xiaochun Bai

DOI
https://doi.org/10.7554/eLife.89912
Journal volume & issue
Vol. 12

Abstract

Read online

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.

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