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Deregulated mito-nuclear communication alters chromatin plasticity and osteogenic differentiation potential upon ageing in mesenchymal stem cells (MSCs) [ATAC-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: GSE143578 | 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) [RNA-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.

2021-07-08 | GSE143579 | GEO

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

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-07-08 | GSE143580 | GEO

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.

2022-10-18 | GSE200072 | GEO

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

2022-10-18 | GSE200071 | GEO

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

2022-10-18 | GSE200070 | GEO

Cytosolic acetyl-CoA promotes histone acetylation predominantly at H3K27 in Arabidopsis

Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.

2017-09-25 | GSE79524 | GEO

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

Project description:We report that upon ageing MSC exhibit reduced metabolic rates, with lower lipid biosynthesis and elevated acetyl-CoA levels. However, aged cells display chromatin compaction and histone hypo-acetylation, particularly on enhancers of genes involved in osteogenesis. This is due to the lower levels of citrate carrier, resulting in impaired acetyl-CoA export from mitochondria to the cytosol, which concomitantly affects histone acetylation and osteogenesis. CiC gets degraded in the aged cells via an MVD-lysosomal pathway, which establishes a strong connection between mitochondrial quality control, chromatin and stemness.

2021-07-08 | GSE155714 | GEO

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

2021-07-08 | GSE173358 | GEO

Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and long-term memory [RNA-seq]

Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).

2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress

SLC13A5/NaCT overexpression causes disrupted white matter integrity, synaptic dysfunction, and an autistic-like phenotype in the mouse

Project description:Endoplasmic-reticulum (ER)-based N-lysine acetylation is a positive selection marker for properly folded glycoproteins in the early secretory pathway, serving as an important protein quality control system. Excessive N-lysine acetylation within the ER via overexpression of the acetyl-CoA transporter AT-1 results in altered glycoprotein flux through the secretory pathway, which dramatically impacts dendritic branching and spine formation causing an autistic-like phenotype in the mouse. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate synporter, and ATP citrate lyase (ACLY), the cytosolic enzyme that converts citrate into acetyl-CoA, in order to maintain the cytosolic-to-ER flux of acetyl-CoA. As such, we generated the SLC13A5 neuron transgenic (nTg) mouse with the hypothesis that increasing cytosolic citrate would impact acetyl-CoA flux into the ER and recapitulate the autistic-like AT-1 nTg model. Here, we demonstrated the SLC13A5 nTg mouse exhibits autistic-like behaviors with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Finally, analysis of both the proteome and acetylome revealed unique adaptations in the hippocampus and cortex to SLC13A5 overexpression, implicating the importance of metabolic consequences of altered cytosolic citrate/acetyl-CoA availability in the neuron. Overall, our results corroborate the mechanistic link between aberrant intracellular citrate/acetyl-CoA flux and the development of an autistic-like phenotype.

2021-08-26 | PXD026624 | Pride

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