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Deregulated mito-nuclear communication alters chromatin plasticity and osteogenic differentiation potential upon ageing in mesenchymal stem cells (MSCs) [RNA-seq]

ABSTRACT: We report that upon ageing MSC undergo a metabolic switc, down-regulating glycolysis and inducing fatty acid oxidation, which results in elevated acetyl-CoA levels. However, aged cells exhibit chromatin compaction and histone hypo-aceylation. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affetcs histone acetylation and osteogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE143579 | GEO | 2021/07/08

REPOSITORIES: GEO

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Deregulated mito-nuclear communication alters chromatin plasticity and osteogenic differentiation potential upon ageing in mesenchymal stem cells (MSCs) [ATAC-seq]

Project description:We report that upon ageing MSC undergo a metabolic switc, down-regulating glycolysis and inducing fatty acid oxidation, which results in elevated acetyl-CoA levels. However, aged cells exhibit chromatin compaction and histone hypo-aceylation. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affetcs histone acetylation and osteogenesis.

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Deregulated mito-nuclear communication alters chromatin plasticity and osteogenic differentiation potential upon ageing in mesenchymal stem cells (MSCs)

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Hypoxia promotes osteonesis via regulation of the mito-nuclear communication [ATAC-seq]

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The ageing epigenome regulates stem cell fate via mitochondrial-derived vesicles delivery of citrate carrier to lysosomes [CUT&RUN_H3AC]

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ACLY and ACSS2 link nutrient-dependent chromatin accessibility to regulation of CD8 T cell effector responses

Project description:Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme Acly (ATP citrate lyase). However, ablation of Acly triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by Acss2 (acyl-CoA synthetase short chain family member 2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When Acly is functional, Acss2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, deletion of Acly renders CD8 T cells dependent on acetate (via Acss2) to maintain acetyl-CoA production and effector function. Thus, together Acly and Acss2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

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