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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]

Project description:Bone marrow mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. Several studies have highlighted the critical role of hypoxia (low oxygen concentration) in the regulation of stem cell function, reporting differentiation defects following a switch to normoxia (high oxygen concentration). However, the molecular events triggering changes in stem cell fate decisions in response to high oxygen remain elusive. Here, we study the impact of normoxia in the mito-nuclear communication, with regards to stem cell differentiation. We show that normoxia-cultured MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces rewiring of metabolism, resulting in high acetyl-CoA levels, histone hypo-acetylation occurs due to trapping of acetyl-CoA inside mitochondria, likely due to lower CiC activity. Strikingly, restoring the cytosolic acetyl-CoA pool via acetate supplementation remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is heavily perturbed in response to high oxygen and identify CiC as a novel, oxygen-sensitive regulator of MSC function.

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

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

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 ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short chain family member 2 (ACSS2). 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, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. 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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