Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics.

Autor: Longo M; Department of Translational Medicine, Federico II University of Naples, Naples, Italy.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Zatterale F; Department of Translational Medicine, Federico II University of Naples, Naples, Italy.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Spinelli R; Department of Translational Medicine, Federico II University of Naples, Naples, Italy.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Naderi J; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Parrillo L; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Florese P; Department of Translational Medicine, Federico II University of Naples, Naples, Italy., Nigro C; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Leone A; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Moccia A; Department of Translational Medicine, Federico II University of Naples, Naples, Italy., Desiderio A; Department of Translational Medicine, Federico II University of Naples, Naples, Italy.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Raciti GA; Department of Translational Medicine, Federico II University of Naples, Naples, Italy. gregoryalexander.raciti@unina.it.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. gregoryalexander.raciti@unina.it., Miele C; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy., Smith U; Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden., Beguinot F; Department of Translational Medicine, Federico II University of Naples, Naples, Italy. beguino@unina.it.; URT Genomics of Diabetes, Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy. beguino@unina.it.
Jazyk: angličtina
Zdroj: Clinical epigenetics [Clin Epigenetics] 2023 Sep 07; Vol. 15 (1), pp. 144. Date of Electronic Publication: 2023 Sep 07.
DOI: 10.1186/s13148-023-01556-z
Abstrakt: Background: First-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.
Results: Sequencing-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 2 O 2 )-induced senescence, while H 2 O 2 did not affect TFAM expression.
Conclusions: Histone 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.
(© 2023. BioMed Central Ltd., part of Springer Nature.)
Databáze: MEDLINE
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