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ZMAT3 hypomethylati...
ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics
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Spinelli, R. (author)
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Florese, P. (author)
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Parrillo, L. (author)
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show more...
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Zatterale, F. (author)
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Longo, M. (author)
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D'Esposito, V. (author)
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Desiderio, A. (author)
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- Nerstedt, Annika, 1960 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Gustafson, Birgit, 1951 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Formisano, P. (author)
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Miele, C. (author)
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Raciti, G. A. (author)
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Napoli, R. (author)
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- Smith, Ulf, 1943 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Beguinot, F. (author)
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(creator_code:org_t)
- 2022-02-11
- 2022
- English.
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In: Aging Cell. - : Wiley. - 1474-9718 .- 1474-9726. ; 21:3
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https://onlinelibrar...
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
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- Senescence of adipose precursor cells (APC) impairs adipogenesis, contributes to the age-related subcutaneous adipose tissue (SAT) dysfunction, and increases risk of type 2 diabetes (T2D). First-degree relatives of T2D individuals (FDR) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDR more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APC from FDR and individuals with no diabetes familiarity (CTRL), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDR and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APC from FDR individuals revealed increases in multiple senescence markers compared to CTRL. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APC led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APC determined senescence and activation of the p53/p21 pathway, as observed in FDR APC. Adipogenesis was also inhibited in ZMAT3-overexpressing APC. In FDR APC, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, aging and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APC accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDR predisposition for T2D.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- adipose precursor cells
- aging
- cellular senescence
- DNA methylation
- first-degree relatives of type 2 diabetics
- senolytics
- type 2 diabetes
- ZMAT3
- impaired glucose-tolerance
- cellular senescence
- adipose-tissue
- insulin
- sensitivity
- splicing regulator
- tumor suppression
- gene-expression
- p53
- cells
- wig-1
- Cell Biology
- Geriatrics & Gerontology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Aging Cell
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- By the author/editor
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Spinelli, R.
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Florese, P.
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Parrillo, L.
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Zatterale, F.
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Longo, M.
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D'Esposito, V.
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show more...
-
Desiderio, A.
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Nerstedt, Annika ...
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Gustafson, Birgi ...
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Formisano, P.
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Miele, C.
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Raciti, G. A.
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Napoli, R.
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Smith, Ulf, 1943
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Beguinot, F.
-
show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Geriatrics
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Aging Cell
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University of Gothenburg