ArticleClinical epigenetics2023
Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics.
Article in Clinical epigenetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 11 citations in OpenAlex.
- SETD1A Regulates Glycolysis and Senescence of Nucleus Pulposus Cells via H3K4me3-HELZ2/PPARα-HIF1α Axis to Drive Intervertebral Disc Degeneration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting TFAM K76 acetylation attenuates mitochondrial dysfunction and kidney injury in diabetic kidney disease.Cardiovascular diabetology · 2026Article
- Trained immunity as a systemic bridge: the liver-gut-immune-oral axis in the comorbidity of chronic liver disease and periodontitis.Frontiers in immunology · 2026Review
- Stroke in Pregnancy Brings Epigenetic Changes in Correlation with Affected Mitochondrial Dynamics and Inflammasome Mediated Apoptosis in Rodents.Journal of the American Heart Association · 2025Article
- Roles of Lysine Methylation in Glucose and Lipid Metabolism: Functions, Regulatory Mechanisms, and Therapeutic Implications.Biomolecules · 2024Review
- Epigenetic modifications in obesity-associated diseases.MedComm · 2024Review
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundFirst-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.
resultsSequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM-siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM-siRNA significantly expanded hydrogen peroxide (H
conclusionsHistone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
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