Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in muscle stem cells

Age-related tissue alterations have been associated with a decline in stem cell number and function1. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing2-5, little is known about the molecular diversity of stem cells during ageing. Here, by combined single-cell transcriptome and DNA methylome profiling in mouse muscle stem cells, we show a striking global increase of uncoordinated transcriptional heterogeneity together with context-dependent alterations of DNA methylation with age. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. Notably, old cells that change the most with age reveal alterations in the transcription of genes regulating cell-niche interactions. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is a substantial driver of the degradation of coherent transcriptional networks with consequent stem cell functional decline during ageing.