Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus
Abstract Background Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic devel...
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doaj-cde0ea79abce419b92e5cda39d85153e2021-04-18T11:22:13ZengBMCBMC Endocrine Disorders1472-68232021-04-012111710.1186/s12902-021-00739-0Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitusLiangcai Ding0Mengdi Cai1Lu Chen2Han Yan3Shicheng Lu4Shuchao Pang5Bo Yan6Center for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical UniversityCenter for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical UniversityCenter for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical UniversityCenter for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical UniversityDivision of Endocrinology, Yanzhou People’s Hospital, Jining Medical UniversityShandong Provincial Sino-US Cooperation Research Center for Translational Medicine, Affiliated Hospital of Jining Medical University, Jining Medical UniversityCenter for Molecular Medicine, Yanzhou People’s Hospital, Jining Medical UniversityAbstract Background Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. In this study, we aimed to investigate whether regulatory variants in GATA4 gene may change GATA4 levels, conferring susceptibility to T2D development. Methods The promoter region of GATA4 gene was analyzed by targeted sequencing in T2D patients (n = 255) and ethnic-matched controls (n = 371). Dual luciferase activity assay was used for functional study, and EMSA (electrophoretic mobility shift assay) was performed for detecting transcription factor binding. Results Thirteen regulatory variants including 5 SNPs were identified. A novel heterozygous variant (32124C > T) and one SNP [31487C > G (rs1053351749)] were only identified in T2D. Both regulatory variants significantly affected GATA4 gene promoter activity in cultured HEK-293 and INS-1 cells. Furthermore, the variant (32124C > T) evidently enhanced the binding of unknown transcriptional activator. Conclusions Our data suggested that GATA4 gene regulatory variants may contribute to T2D development as a rare risk factor.https://doi.org/10.1186/s12902-021-00739-0Type 2 diabetes mellitusGeneticsGATA4Regulatory variants |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liangcai Ding Mengdi Cai Lu Chen Han Yan Shicheng Lu Shuchao Pang Bo Yan |
spellingShingle |
Liangcai Ding Mengdi Cai Lu Chen Han Yan Shicheng Lu Shuchao Pang Bo Yan Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus BMC Endocrine Disorders Type 2 diabetes mellitus Genetics GATA4 Regulatory variants |
author_facet |
Liangcai Ding Mengdi Cai Lu Chen Han Yan Shicheng Lu Shuchao Pang Bo Yan |
author_sort |
Liangcai Ding |
title |
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus |
title_short |
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus |
title_full |
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus |
title_fullStr |
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus |
title_full_unstemmed |
Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus |
title_sort |
identification and functional study of gata4 gene regulatory variants in type 2 diabetes mellitus |
publisher |
BMC |
series |
BMC Endocrine Disorders |
issn |
1472-6823 |
publishDate |
2021-04-01 |
description |
Abstract Background Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. In this study, we aimed to investigate whether regulatory variants in GATA4 gene may change GATA4 levels, conferring susceptibility to T2D development. Methods The promoter region of GATA4 gene was analyzed by targeted sequencing in T2D patients (n = 255) and ethnic-matched controls (n = 371). Dual luciferase activity assay was used for functional study, and EMSA (electrophoretic mobility shift assay) was performed for detecting transcription factor binding. Results Thirteen regulatory variants including 5 SNPs were identified. A novel heterozygous variant (32124C > T) and one SNP [31487C > G (rs1053351749)] were only identified in T2D. Both regulatory variants significantly affected GATA4 gene promoter activity in cultured HEK-293 and INS-1 cells. Furthermore, the variant (32124C > T) evidently enhanced the binding of unknown transcriptional activator. Conclusions Our data suggested that GATA4 gene regulatory variants may contribute to T2D development as a rare risk factor. |
topic |
Type 2 diabetes mellitus Genetics GATA4 Regulatory variants |
url |
https://doi.org/10.1186/s12902-021-00739-0 |
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