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MRG15 alternative splicing regulates CDK1 transcriptional activity in mouse cell senescence and myocardial

Yuan Zhang1,2,3, Huayu Wang1, Fang Li1

  • 1Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Communications Biology
|June 7, 2025
PubMed

Insights

The splice variant MRG15L accumulates with age, promoting cellular senescence and impairing cardiac repair. Targeting MRG15L may offer new therapies for age-related diseases and enhance heart regeneration.

Area of Science:

  • Molecular Biology
  • Gerontology
  • Cardiovascular Research

Background:

  • The chromatin remodeling protein MRG15 is implicated in cellular senescence and proliferation.
  • The specific roles and mechanisms of MRG15 in aging regulation are not fully understood.
  • Alternative splicing generates different MRG15 variants with potentially distinct functions.

Purpose of the Study:

  • To elucidate the distinct functions of MRG15 splice variants in aging.
  • To investigate the role of MRG15L in cellular senescence and cardiac aging.
  • To assess MRG15L as a potential therapeutic target for age-related cardiovascular conditions.

Main Methods:

  • Histone peptide binding assays to assess protein-histone interactions.
  • Protein interaction analysis to identify binding partners.
  • In vivo studies using mouse models of cardiac injury and aging.

Main Results:

  • MRG15L, not MRG15S, accumulates with age.
  • MRG15L shows reduced binding to acetylated histone H4, weakening CDK1 regulation and causing G2/M arrest, thus promoting senescence.
  • Increased MRG15L during cardiac development correlates with reduced regenerative capacity.
  • MRG15L knockout in mice improves cardiac repair after ischemia-reperfusion injury.

Conclusions:

  • MRG15L plays a critical role in promoting cellular senescence and impairing cardiac regeneration during aging.
  • Alternative splicing of MRG15 significantly impacts aging pathways.
  • MRG15L is a potential therapeutic target for age-related diseases, particularly for enhancing cardiac repair.

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