Longo, Michele (2017) Epigenetic modifications of the ZNF423 gene control adipogenic commitment and are dysregulated in human hypertrophic obesity. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Lingua: English
Title: Epigenetic modifications of the ZNF423 gene control adipogenic commitment and are dysregulated in human hypertrophic obesity
Longo, Michelemi_longo@libero.it
Date: 10 December 2017
Number of Pages: 59
Institution: Università degli Studi di Napoli Federico II
Department: dep22
Dottorato: phd053
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
Marone, Giannimarone@unina.it
Beguinot, FrancescoUNSPECIFIED
Date: 10 December 2017
Number of Pages: 59
Uncontrolled Keywords: Epigenetics, Diabetes, Obesity
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/11 - Biologia molecolare
Area 06 - Scienze mediche > MED/04 - Patologia generale
Area 06 - Scienze mediche > MED/13 - Endocrinologia
Date Deposited: 21 Dec 2017 10:06
Last Modified: 22 Mar 2019 10:51
URI: http://www.fedoa.unina.it/id/eprint/12163


Subcutaneous adipocyte hypertrophy is typically associated with insulin resistance and increased risk of type 2 diabetes and predicts its future development independent of obesity. In humans, subcutaneous adipose tissue hypertrophy is a consequence of impaired adipocyte precursor cell recruitment into the adipogenic pathway rather than lack of precursor cells but the molecular events responsible for the restricted adipogenesis remain unclear. The zinc-finger transcription factor (Zfp) 423 has been identified as a major determinant of preadipocyte commitment and maintained white adipose cell function. Although its levels do not change during adipogenesis, ectopic expression of Zfp423 in non-adipogenic cells is sufficient to activate peroxisome proliferator-activated receptor gamma (Pparγ) expression and to increase the adipogenic potential of these cells. In the present work, we have investigated whether Zfp423 is epigenetically regulated and whether these events are involved in the restricted adipogenesis in humans with expanded subcutaneous adipose tissue. We report here that, comparison of uncommitted (NIH-3T3) and committed (3T3-L1) adipose precursor cells revealed that Zfp423 expression increased in parallel with the ability of the cells to differentiate into mature adipocytes owing to both decreased promoter DNA methylation and nucleosome occupancy in the 3T3-L1 compared with NIH-3T3 cells. Interestingly, non-adipogenic epigenetic profiles can be reverted in NIH-3T3 cells as 5-azacytidine treatment increased Zfp423 mRNA levels, reduced DNA methylation at a specific CpG site, decreased nucleosome occupancy and induced adipocyte differentiation. These epigenetic modifications can also be initiated in response to changes in the pre-adipose cell microenvironment, in which bone morphogenetic protein 4 (Bmp4) plays a key role. We finally showed that, expression of the ZNF423 human ortholog in adipocyte precursor cells from subcutaneous adipose tissue inversely correlated to cell size of the autologous mature adipocytes. Promoter methylation at the ZNF423 regulatory region also reflected inappropriate subcutaneous adipose cell hypertrophy. As in NIH-3T3 cells, the normal ZNF423 epigenetic profile was rescued by 5-azacytidine exposure. Thus, our results show that epigenetic events regulate the ability of precursor cells to commit and differentiate into mature adipocytes by modulating ZNF423 expression, and indicate that dysregulation of these mechanisms accompanies subcutaneous adipose tissue hypertrophy in humans.


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