Zhang Yuan, Wang Huayu, Li Fang, Dai Hui, Zhang Ye
Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Faculty of Hepato-Pancreato-Biliary Surgery, the First Medical Center, Chinese PLA General Hospital, Institute of Hepatobiliary Surgery of Chinese PLA, Key Laboratory of Digital Hepatobiliary Surgery, PLA, Beijing, China.
Commun Biol. 2025 Jun 7;8(1):895. doi: 10.1038/s42003-025-08309-z.
MRG15, a chromatin remodeling protein, plays a pivotal role in cellular senescence and proliferation. However, the precise roles and mechanisms of MRG15 in aging regulation remain unclear. Our research elucidates the distinct functions of MRG15's splice variants in aging. We find that MRG15L, contrary to the previously assumed MRG15S, accumulates with advancing age. Using histone peptide binding assays and protein interaction analysis, we demonstrate that MRG15L exhibits reduced affinity for histone H4 acetylation sites, thereby weakening CDK1 regulation, leading to G2/M phase arrest and promoting cellular senescence. During postnatal cardiac development, MRG15L expression increases and is linked to reduced regenerative capacity. Moreover, targeted knockout of MRG15L in mice enhances cardiac repair and regeneration following myocardial ischemia-reperfusion injury. These findings highlight MRG15L as a promising therapeutic target for age-related diseases, revealing its critical role in modulating aging pathways through alternative splicing.
MRG15是一种染色质重塑蛋白，在细胞衰老和增殖中起关键作用。然而，MRG15在衰老调控中的具体作用和机制仍不清楚。我们的研究阐明了MRG15剪接变体在衰老中的不同功能。我们发现，与之前假设的MRG15S相反，MRG15L会随着年龄的增长而积累。通过组蛋白肽结合试验和蛋白质相互作用分析，我们证明MRG15L对组蛋白H4乙酰化位点的亲和力降低，从而削弱了CDK1的调控，导致G2/M期阻滞并促进细胞衰老。在出生后心脏发育过程中，MRG15L表达增加，并与再生能力降低有关。此外，在小鼠中靶向敲除MRG15L可增强心肌缺血再灌注损伤后的心脏修复和再生能力。这些发现突出了MRG15L作为与年龄相关疾病的一个有前景的治疗靶点，揭示了其通过可变剪接在调节衰老途径中的关键作用。
