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

Irene Hernando-Herraez (), Brendan Evano, Thomas Stubbs, Pierre-Henri Commere, Marc Bonder, Stephen Clark, Simon Andrews, Shahragim Tajbakhsh () and Wolf Reik ()
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Irene Hernando-Herraez: Babraham Institute
Brendan Evano: Institut Pasteur
Thomas Stubbs: Babraham Institute
Pierre-Henri Commere: Institut Pasteur
Marc Bonder: Wellcome Genome Campus
Stephen Clark: Babraham Institute
Simon Andrews: Babraham Institute
Shahragim Tajbakhsh: Institut Pasteur
Wolf Reik: Babraham Institute

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Age-related tissue alterations have been associated with a decline in stem cell number and function. Although increased cell-to-cell variability in transcription or epigenetic marks has been proposed to be a major hallmark of ageing, little is known about the molecular diversity of stem cells during ageing. Here we present a single cell multi-omics study of mouse muscle stem cells, combining single-cell transcriptome and DNA methylome profiling. Aged cells show a global increase of uncoordinated transcriptional heterogeneity biased towards genes regulating cell-niche interactions. We find context-dependent alterations of DNA methylation in aged stem cells. Importantly, promoters with increased methylation heterogeneity are associated with increased transcriptional heterogeneity of the genes they drive. These results indicate that epigenetic drift, by accumulation of stochastic DNA methylation changes in promoters, is associated with the degradation of coherent transcriptional networks during stem cell ageing. Furthermore, our observations also shed light on the mechanisms underlying the DNA methylation clock.

Date: 2019
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DOI: 10.1038/s41467-019-12293-4

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