YY1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells. (12th April 2019)

• Record Type: Journal Article
• Authors: Chen, Fengyuan; Zhou, Jiajian; Li, Yuying; Zhao, Yu; Yuan, Jie; Cao, Yang; Wang, Lijun; Zhang, Zongkang; Zhang, Baoting; Wang, Chi Chiu; Cheung, Tom H; Wu, Zhenguo; Wong, Carmen Chak‐Lui; Sun, Hao; Wang, Huating
• Is Part Of: EMBO journal. Volume 38:Number 10(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-12
• Subjects: Hif1α -- metabolic reprogramming -- muscle satellite cell -- skeletal muscle regeneration -- YY1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201899727
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Skeletal muscle satellite cells (SCs) are adult muscle stem cells responsible for muscle regeneration after acute or chronic injuries. The lineage progression of quiescent SC toward activation, proliferation, and differentiation during the regeneration is orchestrated by cascades of transcription factors (TFs). Here, we elucidate the function of TF Yin Yang1 (YY1) in muscle regeneration. Muscle‐specific deletion of YY1 in embryonic muscle progenitors leads to severe deformity of diaphragm muscle formation, thus neonatal death. Inducible deletion of YY1 in SC almost completely blocks the acute damage‐induced muscle repair and exacerbates the chronic injury‐induced dystrophic phenotype. Examination of SC revealed that YY1 loss results in cell‐autonomous defect in activation and proliferation. Mechanistic search revealed that YY1 binds and represses mitochondrial gene expression. Simultaneously, it also stabilizes Hif1α protein and activates Hif1α‐mediated glycolytic genes to facilitate a metabolic reprogramming toward glycolysis which is needed for SC proliferation. Altogether, our findings have identified YY1 as a key regulator of SC metabolic reprogramming through its dual roles in modulating both mitochondrial and glycolytic pathways. Synopsis: Combining genetic mouse models and global expression profiling, the transcription factor YinYang1 (YY1) is shown to exert binary roles in muscle stem cells to switch energy metabolism and allow for expansion during muscle development and injury response. Conditional deletion of YY1 in Pax7‐expressing muscle progenitor cells causes defective muscle development and early postnatal death. Inducible ablation of YY1 in adult muscle impairs acute injury induced muscle regeneration and aggravates chronic stress in muscular dystrophy mice. YY1 deletion effects are cell‐autonomous and reduce muscle stem cell activation and proliferation. YY1 represses expression of mitochondrial genes in stem cells. YY1 activates glycolytic genes during stem cell activation via increasing Hif1α protein stability. Abstract : The transcription factor YY1 exerts binary roles in satellite cell energy metabolism and mitochondrial function during muscle development and in response to injury.