Apr 3, 2020

Deregulated mito-nuclear communication alters chromatin plasticity and differentiation potential of mesenchymal stem cells upon ageing

BioRxiv : the Preprint Server for Biology
A. PouikliPeter Tessarz

Abstract

Ageing is accompanied by a general decline in the function of many cellular pathways, with metabolic alterations, epigenetic modifications, and stem cell exhaustion representing three important hallmarks of the ageing process. However, whether these pathways are causally or functionally related at a molecular level remains poorly understood. Here, we use bone marrow-derived mesenchymal stem cells (MSCs) isolated from young and old mice to address how age-dependent changes in metabolism and epigenetics are linked and how they impact on the ageing transcriptome and differentiation potential. Given that MSCs maintain specific age-associated properties even under prolonged culture conditions, such as the age-dependent decrease in osteogenic differentiation, they are an excellent model to investigate in vitro the connection of ageing hallmarks on a mechanistic level. In this study, we demonstrate that upon ageing, osteogenic potential of MSCs declines as a consequence of deregulated mito-nuclear communication, mediated by decreased levels of the citrate carrier (CiC). Age-dependent down-regulation of CiC results in acetyl-CoA trapping within mitochondria, hypo-acetylation of histones and chromatin compaction. Together, these changes...Continue Reading

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Mentioned in this Paper

Chromatin Loop
Protein Binding
2-Dimensional
Heuristics
Protein Methylation
Genome
Genes
Three-dimensional
Promoter
Genes, Regulator

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