Florese, Pasqualina (2023) HYPOMETHYLATION OF THE P53-TARGET ZMAT3 IS ASSOCIATED WITH SENESCENCE OF SUBCUTANEOUS ADIPOCYTE PRECURSOR CELLS IN INDIVIDUALS WITH A FAMILY HISTORY OF TYPE 2 DIABETES. [Tesi di dottorato]
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| Item Type: | Tesi di dottorato |
|---|---|
| Resource language: | English |
| Title: | HYPOMETHYLATION OF THE P53-TARGET ZMAT3 IS ASSOCIATED WITH SENESCENCE OF SUBCUTANEOUS ADIPOCYTE PRECURSOR CELLS IN INDIVIDUALS WITH A FAMILY HISTORY OF TYPE 2 DIABETES |
| Creators: | Creators Email Florese, Pasqualina lina.florese@gmail.com |
| Date: | March 2023 |
| Number of Pages: | 104 |
| Institution: | Università degli Studi di Napoli Federico II |
| Department: | Scienze Mediche Traslazionali |
| Dottorato: | Medicina clinica e sperimentale |
| Ciclo di dottorato: | 35 |
| Coordinatore del Corso di dottorato: | nome email Beguinot, Francesco beguino@unina.it |
| Tutor: | nome email Beguinot, Francesco beguino@unina.it |
| Date: | March 2023 |
| Number of Pages: | 104 |
| Keywords: | ZMAT3,CELLULAR SENESCENCE, FIRST DEGREE RELATIVES OF TYPE 2 DIABETES |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/05 - Patologia clinica |
| Date Deposited: | 25 Mar 2024 11:28 |
| Last Modified: | 25 Mar 2024 11:28 |
| URI: | http://www.fedoa.unina.it/id/eprint/14968 |
Collection description
Senescence of adipose precursor cells (APCs) 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 (FDRs) feature restricted adipogenesis, reflecting the detrimental effects of APC senescence earlier in life and rendering FDRs more vulnerable to T2D. Epigenetics may contribute to these abnormalities but the underlying mechanisms remain unclear. In previous methylome comparison in APCs from FDRs and individuals with no diabetes familiarity (CTRLs), ZMAT3 emerged as one of the top-ranked senescence-related genes featuring hypomethylation in FDRs and associated with T2D risk. Here, we investigated whether and how DNA methylation changes at ZMAT3 promote early APC senescence. APCs from FDR individuals revealed increases in multiple senescence markers compared to CTRLs. Senescence in these cells was accompanied by ZMAT3 hypomethylation, which caused ZMAT3 upregulation. Demethylation at this gene in CTRL APCs led to increased ZMAT3 expression and premature senescence, which were reverted by ZMAT3 siRNA. Furthermore, ZMAT3 overexpression in APCs determined senescence and activation of the p53/p21 pathway, as observed in FDR APCs. Adipogenesis was also inhibited in ZMAT3-overexpressing APCs. In FDR APCs, rescue of ZMAT3 methylation through senolytic exposure simultaneously downregulated ZMAT3 expression and improved adipogenesis. Interestingly, in human SAT, ageing and T2D were associated with significantly increased expression of both ZMAT3 and the P53 senescence marker. Thus, DNA hypomethylation causes ZMAT3 upregulation in FDR APCs accompanied by acquisition of the senescence phenotype and impaired adipogenesis, which may contribute to FDRs predisposition for T2D.
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