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Sökning: WFRF:(Zatterale A.) > (2020-2023) > Altered H3K4me3 pro...

LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004021naa a2200493 4500
001oai:gup.ub.gu.se/335451
003SwePub
008240528s2023 | |||||||||||000 ||eng|
0247 a https://gup.ub.gu.se/publication/3354512 URI
0247 a https://doi.org/10.1186/s13148-023-01556-z2 DOI
040 a (SwePub)gu
041 a eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Longo, Michele4 aut
2451 0a Altered H3K4me3 profile at the TFAM promoter causes mitochondrial alterations in preadipocytes from first-degree relatives of type 2 diabetics
264 1c 2023
520 a 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 (H2O2)-induced senescence, while H2O2 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.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
653 a Type 2 diabetes
653 a Adipose tissue dysfunction
653 a Epigenetic mechanisms
653 a Mitochondrial alterations
653 a Adipogenesis
653 a Premature senescence
7001 a Zatterale, Federica4 aut
7001 a Spinelli, Rosa4 aut
7001 a Naderi, Jamal4 aut
7001 a Parrillo, Luca4 aut
7001 a Florese, Pasqualina4 aut
7001 a Nigro, Cecilia4 aut
7001 a Leone, Alessia4 aut
7001 a Moccia, Augusta4 aut
7001 a Desiderio, Antonella4 aut
7001 a Raciti, Gregory A.4 aut
7001 a Miele, Claudia4 aut
7001 a Smith, Ulf,d 1943u Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine4 aut0 (Swepub:gu)xsmiul
7001 a Beguinot, Francesco4 aut
7102 a Göteborgs universitetb Institutionen för medicin, avdelningen för molekylär och klinisk medicin4 org
7730 t CLINICAL EPIGENETICSg 15:1q 15:1x 1868-7075x 1868-7083
8564 8u https://gup.ub.gu.se/publication/335451
8564 8u https://doi.org/10.1186/s13148-023-01556-z

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