Ageing affects DNA methylation and transcriptional cell-to-cell variability in muscle stem cells [scRNA-seq]

Age-related tissue alterations have been associated with a decline in stem cell number and function. Increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing. Here, using parallel single-cell transcriptome and DNA methylome profiling, we find a global increase of uncoordinated transcriptional heterogeneity and context-dependent alterations of DNA methylation heterogeneity in ageing mouse muscle stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. Notably, old cells diverging from young cells revealed alterations in the transcription of multiple extracellular matrix related genes. These findings show linked increases in heterogeneity between the epigenome and the transcriptome, with attendant degradation of coherent transcriptional networks and stem cell functional decline during ageing. 5 young and 3 old mice.

与年龄相关的组织退变，与干细胞数量减少及功能衰退密切相关。转录或表观遗传标记层面的细胞间异质性升高，被认为是衰老的核心特征之一。本研究通过平行单细胞转录组与DNA甲基化组联合谱型分析，对衰老小鼠肌肉干细胞展开探究，发现衰老小鼠肌肉干细胞中存在全局性的转录异质性失调升高，以及DNA甲基化异质性的情境依赖性改变。值得注意的是，甲基化异质性升高的启动子，与其所调控基因的转录异质性升高显著相关。尤为关键的是，与年轻细胞相比，衰老细胞呈现出多个细胞外基质相关基因的转录异常。本研究结果表明，衰老过程中表观基因组与转录组的异质性呈现协同升高趋势，伴随连贯转录调控网络的紊乱，以及干细胞功能的衰退。本实验所用小鼠为5只年轻个体与3只衰老个体。