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

Published version
Peer-reviewed

Type

Article

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Authors

Hernando-Herraez, Irene 
Evano, Brendan 
Stubbs, Thomas 
Commere, Pierre-Henri 
Jan Bonder, Marc 

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.

Description

Keywords

Aging, Animals, Cells, Cultured, Cellular Senescence, DNA Methylation, Epigenesis, Genetic, Epigenomics, Gene Expression Profiling, Gene Ontology, Humans, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Muscles, Promoter Regions, Genetic, Single-Cell Analysis, Stem Cells, Transcriptome

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

10

Publisher

Springer Nature
Sponsorship
Includes ERC and BBSRC
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