A. Dong

Significance Epigenetic regulations control the accessibility of transcription factors to their target regions. Modulation of chromatin accessibility determines which transcripts to be expressed and therefore, defines cell identity. Chromatin modulation during cell fate determination involves a complex regulatory network, yet the comprehensive view remains to be explored. Here, we provide a global view of chromatin accessibility during muscle stem cell activation. We identified a long noncoding RNA (lncRNA), LncMyoD , which regulates lineage determination and progression through modulating chromatin accessibility. Functional analysis showed that loss of LncMyoD strongly impairs reprogramming of fibroblasts into myogenic lineage and causes defects in muscle stem cell differentiation. Our findings provide an epigenetic mechanism for the regulation of muscle stem cell myogenic lineage progression by an lncRNA.

chromatin states, we utilized the PFA-perfusion-based isolation approach and characterized the DNA regulatory landscapes during muscle stem cell quiescence exit and aging. We showed that aged SCs display a chronically activated chromatin signature. Detailed analysis of the chromatin accessibility profiles identified key enhancer elements for SC quiescence. Constant activation of the enhancer elements promotes stemness and prevents SCs from differentiation, whereas genetic deletion causes cell-cycle arrest and leads to defects in activation. Our comprehensive characterization of the chromatin accessibility and transcriptomic landscapes in SC quiescence and aging broadens our understanding of these processes and identifies key distal regulatory elements for SC function.

Age-associated impairments in adult stem cell functions correlate with a decline in somatic tissue regeneration capacity. However, the mechanisms underlying the molecular regulation of adult stem cell aging remain elusive. Here, we provide a proteomic analysis of physiologically aged murine muscle stem cells (MuSCs), illustrating a pre-senescent proteomic signature. During aging, the mitochondrial proteome and activity are impaired in MuSCs. In addition, the inhibition of mitochondrial function results in cellular senescence. We identified an RNA-binding protein, CPEB4, downregulated in various aged tissues, which is required for MuSC functions. CPEB4 regulates the mitochondrial proteome and activity through mitochondrial translational control. MuSCs devoid of CPEB4 induced cellular senescence. Importantly, restoring CPEB4 expression rescued impaired mitochondrial metabolism, improved geriatric MuSC functions, and prevented cellular senescence in various human cell lines. Our findings provide the basis for the possibility that CPEB4 regulates mitochondrial metabolism to govern cellular senescence, with an implication of therapeutic intervention for age-related senescence.