Similar Datasets
Project description: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.
| S-EPMC6761124 | biostudies-literature
Project description: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.
2019-08-22 | GSE121436 | GEO
Project description: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.
2019-08-14 | GSE121364 | GEO
Project description:Ageing affects DNA methylation and transcriptional cell-to-cell variability in muscle stem cells
| PRJNA497311 | ENA
Project description:Ageing affects DNA methylation and transcriptional cell-to-cell variability in muscle stem cells [scBS-seq]
| PRJNA497312 | ENA
Project description:Ageing affects DNA methylation and transcriptional cell-to-cell variability in muscle stem cells [scRNA-seq]
| PRJNA497128 | ENA
Project description:Injury to muscle brings about the activation of stem cells, which then generate new myocytes to replace damaged tissue. We demonstrate that this activation is accompanied by a dramatic change in the stem-cell methylation pattern that prepares them epigenetically for terminal myocyte differentiation. These de- and de novo methylation events occur at regulatory elements associated with genes involved in myogenesis and are necessary for activation and regeneration. Local injury of one muscle elicits an almost identical epigenetic change in satellite cells from other muscles in the body, in a process mediated by circulating factors. Furthermore, this same methylation state is also generated in muscle stem cells (MuSCs) of female animals following pregnancy, even in the absence of any injury. Unlike the activation-induced expression changes, which are transient, the induced methylation profile is stably maintained in resident MuSCs and thus represents a molecular memory of previous physiological events that is probably programmed to provide a mechanism for long-term adaptation.
| S-EPMC9907067 | biostudies-literature
Project description:The functionality of stem cells declines during ageing, and this decline contributes to ageing-associated impairments in tissue regeneration and function. Alterations in developmental pathways have been associated with declines in stem-cell function during ageing, but the nature of this process remains poorly understood. Hox genes are key regulators of stem cells and tissue patterning during embryogenesis with an unknown role in ageing. Here we show that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways include most of the currently known inhibitors of satellite cell function in ageing muscle, including Wnt, TGF?, JAK/STAT and senescence signalling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics ageing-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineate an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.
| S-EPMC5415306 | biostudies-literature
Project description:Understanding cell-to-cell variability in cytosine methylation is essential for understanding cellular perturbation and its molecular machinery. However, conventional methylation studies have focused on the differences in the average levels between cell types while overlooking methylation heterogeneity within cell types. Little information has been uncovered using recent single-cell methods because of either technical limitations or the great labor required to process many single cells. Here, we report the highly efficient detection of cell-to-cell DNA methylation variability in liver tissue, based on comparing the methylation status of adjacent CpG sites on long sequencing reads. This method provides abundant methylation linkage information and enables genome-wide estimation of cell-to-cell variability. We observed repressed methylation variability in hypomethylated regions compared with the variability in hypomethylated regions across the genome, which we confirmed using public human sperm data. A gradual change in methylation status at the boundaries of hypomethylated regions was observed for the first time. This approach allows the concise, comprehensive assessment of cell-to-cell DNA methylation variability.
| S-EPMC4758075 | biostudies-literature
Project description:Persistently unrepaired DNA damage has been identified as a causative factor for vascular ageing. We have previously shown that a defect in the function or expression of the DNA repair endonuclease ERCC1 (excision repair cross complement 1) in mice leads to accelerated, nonatherosclerotic ageing of the vascular system from as early as 8 weeks after birth. Removal of ERCC1 from endothelial alone partly explains this ageing, as shown in endothelial-specific Ercc1 knockout mice. In this study, we determined vascular ageing due to DNA damage in vascular smooth muscle cells, as achieved by smooth muscle-selective genetic removal of ERCC1 DNA repair in mice (SMC-KO: SM22αCre+ Ercc1fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22αCre+ Ercc1fl/+) were examined at the age of 14 weeks and 25 weeks. Both SMC-KO and WT mice were normotensive. Compared to WT, SMC-KO showed a reduced heart rate, fractional shortening, and cardiac output. SMC-KO showed progressive features of nonatherosclerotic vascular ageing as they aged from 14 to 25 weeks. Decreased subcutaneous microvascular dilatation and increased carotid artery stiffness were observed. Vasodilator responses measured in aortic rings in organ baths showed decreased endothelium-dependent and endothelium-independent responses, mostly due to decreased NO-cGMP signaling. NADPH oxidase 2 and phosphodiesterase 1 inhibition improved dilations. SMC-KO mice showed elevated levels of various cytokines that indicate a balance shift in pro- and anti-inflammatory pathways. In conclusion, SMC-KO mice showed a progressive vascular ageing phenotype in resistant and conduit arteries that is associated with cardiac remodeling and contractile dysfunction. The changes induced by DNA damage might be limited to VSMC but eventually affect EC-mediated responses. The fact that NADPH oxidase 2 as wells as phosphodiesterase 1 inhibition restores vasodilation suggests that both decreased NO bioavailability and cGMP degradation play a role in local vascular smooth muscle cell ageing induced by DNA damage.
| S-EPMC8423575 | biostudies-literature