Cargando…

Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis

Peroxisome proliferator-activated receptor γ2 (PPARγ2) is a nuclear hormone receptor of ligand-dependent transcription factor with a key role in adipogenesis and insulin sensitization in diabetes mellitus. In this study, we investigated genetic variants in PPARγ2 promoter, its association with gesta...

Descripción completa

Detalles Bibliográficos
Autores principales: Wu, Ling, Song, Yi, Zhang, Yuan, Liang, Bo, Deng, Yan, Tang, Tao, Ye, Yan Chou, Hou, Hong Ying, Wang, Chi Chiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862745/
https://www.ncbi.nlm.nih.gov/pubmed/33551986
http://dx.doi.org/10.3389/fendo.2020.499788
_version_ 1783647355867758592
author Wu, Ling
Song, Yi
Zhang, Yuan
Liang, Bo
Deng, Yan
Tang, Tao
Ye, Yan Chou
Hou, Hong Ying
Wang, Chi Chiu
author_facet Wu, Ling
Song, Yi
Zhang, Yuan
Liang, Bo
Deng, Yan
Tang, Tao
Ye, Yan Chou
Hou, Hong Ying
Wang, Chi Chiu
author_sort Wu, Ling
collection PubMed
description Peroxisome proliferator-activated receptor γ2 (PPARγ2) is a nuclear hormone receptor of ligand-dependent transcription factor with a key role in adipogenesis and insulin sensitization in diabetes mellitus. In this study, we investigated genetic variants in PPARγ2 promoter, its association with gestational diabetes mellitus (GDM), and its molecular regulation. PPARγ2 promoter and start codon (-2,091 to +82 bp) from 400 pregnancies with GDM and 400 gestational-age matched control pregnancies were sequenced. Association and linkage disequilibrium of the identified polymorphisms with GDM was determined. ChIP-seq, gene silencing, and dual-luciferase reporter assays were performed to confirm transcription factor binding sites and promoter activity of the variants. Transfection experiments were carried out to determine the effects of variants on gene expression and adipogenesis. Among 15 variants identified, 7 known variants were not significantly associated with the risk of GDM (odds ratio: 0.710–1.208, 95% confidence interval: 0.445–0.877 to 1.132–1.664, P > 0.05) while linkage disequilibrium was significant (D’ > 0.7, R(2) > 0.9). However, T-A-A-T-G haplotype was not significantly associated with GDM (χ(2) = 2.461, P = 0.117). Five rare variants and 3 novel variants (rs948820149, rs1553638909, and rs1553638903) were only found in GDM. Transcription factor glucocorticoid receptor β (GRβ) bound to -807A/C (rs948820149) and knockdown of GRβ suppressed PPARγ2 promoter activity. This mutation significantly down-regulated PPARγ2 expression and alleviated adipogenesis. In conclusion, a novel -807A/C in PPARγ2 promoter was identified in Chinese women with GDM and the mutation affected GRβ binding and transcription of PPARγ2 for adipogenesis.
format Online
Article
Text
id pubmed-7862745
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-78627452021-02-06 Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis Wu, Ling Song, Yi Zhang, Yuan Liang, Bo Deng, Yan Tang, Tao Ye, Yan Chou Hou, Hong Ying Wang, Chi Chiu Front Endocrinol (Lausanne) Endocrinology Peroxisome proliferator-activated receptor γ2 (PPARγ2) is a nuclear hormone receptor of ligand-dependent transcription factor with a key role in adipogenesis and insulin sensitization in diabetes mellitus. In this study, we investigated genetic variants in PPARγ2 promoter, its association with gestational diabetes mellitus (GDM), and its molecular regulation. PPARγ2 promoter and start codon (-2,091 to +82 bp) from 400 pregnancies with GDM and 400 gestational-age matched control pregnancies were sequenced. Association and linkage disequilibrium of the identified polymorphisms with GDM was determined. ChIP-seq, gene silencing, and dual-luciferase reporter assays were performed to confirm transcription factor binding sites and promoter activity of the variants. Transfection experiments were carried out to determine the effects of variants on gene expression and adipogenesis. Among 15 variants identified, 7 known variants were not significantly associated with the risk of GDM (odds ratio: 0.710–1.208, 95% confidence interval: 0.445–0.877 to 1.132–1.664, P > 0.05) while linkage disequilibrium was significant (D’ > 0.7, R(2) > 0.9). However, T-A-A-T-G haplotype was not significantly associated with GDM (χ(2) = 2.461, P = 0.117). Five rare variants and 3 novel variants (rs948820149, rs1553638909, and rs1553638903) were only found in GDM. Transcription factor glucocorticoid receptor β (GRβ) bound to -807A/C (rs948820149) and knockdown of GRβ suppressed PPARγ2 promoter activity. This mutation significantly down-regulated PPARγ2 expression and alleviated adipogenesis. In conclusion, a novel -807A/C in PPARγ2 promoter was identified in Chinese women with GDM and the mutation affected GRβ binding and transcription of PPARγ2 for adipogenesis. Frontiers Media S.A. 2021-01-22 /pmc/articles/PMC7862745/ /pubmed/33551986 http://dx.doi.org/10.3389/fendo.2020.499788 Text en Copyright © 2021 Wu, Song, Zhang, Liang, Deng, Tang, Ye, Hou and Wang http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Wu, Ling
Song, Yi
Zhang, Yuan
Liang, Bo
Deng, Yan
Tang, Tao
Ye, Yan Chou
Hou, Hong Ying
Wang, Chi Chiu
Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title_full Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title_fullStr Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title_full_unstemmed Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title_short Novel Genetic Variants of PPARγ2 Promoter in Gestational Diabetes Mellitus and its Molecular Regulation in Adipogenesis
title_sort novel genetic variants of pparγ2 promoter in gestational diabetes mellitus and its molecular regulation in adipogenesis
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862745/
https://www.ncbi.nlm.nih.gov/pubmed/33551986
http://dx.doi.org/10.3389/fendo.2020.499788
work_keys_str_mv AT wuling novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT songyi novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT zhangyuan novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT liangbo novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT dengyan novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT tangtao novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT yeyanchou novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT houhongying novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis
AT wangchichiu novelgeneticvariantsofpparg2promoteringestationaldiabetesmellitusanditsmolecularregulationinadipogenesis