ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics

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Spinelli, R. (author)

ZMAT3 hypomethylation contributes to early senescence of preadipocytes from healthy first-degree relatives of type 2 diabetics

Article/chapterEnglish2022

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2022-02-11
Wiley,2022

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LIBRIS-ID:oai:gup.ub.gu.se/314219
https://gup.ub.gu.se/publication/314219URI
https://doi.org/10.1111/acel.13557DOI

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Language:English

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Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

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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 and genre

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
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

Added entries (persons, corporate bodies, meetings, titles ...)

Florese, P. (author)
Parrillo, L. (author)
Zatterale, F. (author)
Longo, M. (author)
D'Esposito, V. (author)
Desiderio, A. (author)
Nerstedt, Annika,1960Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xneran (author)
Gustafson, Birgit,1951Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xgustb (author)
Formisano, P. (author)
Miele, C. (author)
Raciti, G. A. (author)
Napoli, R. (author)
Smith, Ulf,1943Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine(Swepub:gu)xsmiul (author)
Beguinot, F. (author)
Göteborgs universitetInstitutionen för medicin, avdelningen för molekylär och klinisk medicin (creator_code:org_t)

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In:Aging Cell: Wiley21:31474-97181474-9726

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By the author/editor: Spinelli, R.; Florese, P.; Parrillo, L.; Zatterale, F.; Longo, M.; D'Esposito, V.; show more...; Desiderio, A.; Nerstedt, Annika ...; Gustafson, Birgi ...; Formisano, P.; Miele, C.; Raciti, G. A.; Napoli, R.; Smith, Ulf, 1943; Beguinot, F.; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Geriatrics

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