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BMC Endocrine Disorders

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Open Access 01-12-2021 | Diabetes | Research article

Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus

Authors: Liangcai Ding, Mengdi Cai, Lu Chen, Han Yan, Shicheng Lu, Shuchao Pang, Bo Yan

Published in: BMC Endocrine Disorders | Issue 1/2021

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.

Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383(9922):1068–83. https://doi.org/10.1016/S0140-6736(13)62154-6.CrossRefPubMed

Langenberg C, Lotta LA. Genomic insights into the causes of type 2 diabetes. Lancet. 2018;391(10138):2463–74. https://doi.org/10.1016/S0140-6736(18)31132-2.CrossRefPubMed

Steinthorsdottir V, Thorleifsson G, Sulem P, Helgason H, Grarup N, Sigurdsson A, et al. Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. Nat Genet. 2014;46(3):294–8. https://doi.org/10.1038/ng.2882.

Udler MS. Type 2 Diabetes: Multiple Genes, Multiple Diseases. Curr Diab Rep. 2019;19(8):55. https://doi.org/10.1007/s11892-019-1169-7.CrossRefPubMedPubMedCentral

Molkentin JD. The zinc finger-containing transcription factors GATA-4, −5, and −6. Ubiquitously expressed regulators tissue-specific gene expression. J Biol Chem. 2000;275(50):38949–52. https://doi.org/10.1074/jbc.R000029200.CrossRefPubMed

Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397–406. https://doi.org/10.1074/mcp.M113.035600.

Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, et al. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997;11(8):1048–60. https://doi.org/10.1101/gad.11.8.1048.

Molkentin JD, Lin Q, Duncan SA, Olson EN. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 1997;11(8):1061–72. https://doi.org/10.1101/gad.11.8.1061.CrossRefPubMed

Carrasco M, Delgado I, Soria B, Martín F, Rojas A. GATA4 and GATA6 control mouse pancreas organogenesis. J Clin Invest. 2012;122(10):3504–15. https://doi.org/10.1172/JCI63240.CrossRefPubMedPubMedCentral

10.

Xuan S, Borok MJ, Decker KJ, Battle MA, Duncan SA, Hale MA, et al. Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest. 2012;122(10):3516–28. https://doi.org/10.1172/JCI63352.

11.

Rodríguez-Seguel E, Villamayor L, Arroyo N, De Andrés MP, Real FX, Martín F, et al. Loss of GATA4 causes ectopic pancreas in the stomach. J Pathol. 2020;250(4):362–73. https://doi.org/10.1002/path.5378.CrossRefPubMed

12.

Krentz NAJ, Gloyn AL. Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics. Nat Rev Endocrinol. 2020;16(4):202–12. https://doi.org/10.1038/s41574-020-0325-0.CrossRefPubMed

13.

Mattis KK, Gloyn AL. From genetic association to molecular mechanisms for islet-cell dysfunction in type 2 diabetes. J Mol Biol. 2020;432(5):1551–78. https://doi.org/10.1016/j.jmb.2019.12.045.CrossRefPubMed

14.

Letourneau LR, Greeley SAW. Congenital forms of diabetes: the beta-cell and beyond. Curr Opin Genet Dev. 2018;50:25–34. https://doi.org/10.1016/j.gde.2018.01.005.CrossRefPubMedPubMedCentral

15.

Shi ZD, Lee K, Yang D, Amin S, Verma N, Li QV, et al. Genome Editing in hPSCs Reveals GATA6 Haploinsufficiency and a Genetic Interaction with GATA4 in Human Pancreatic Development. Cell Stem Cell. 2017;20:675–88.e6.CrossRef

16.

WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia: a report of WHO/ IDF consultation. Geneva: WHO; 2006.

17.

Wu G, Shan J, Pang S, Wei X, Zhang H, Yan B. Genetic analysis of the promoter region of the GATA4 gene in patients with ventricular septal defects. Transl Res. 2012;159(5):376–82. https://doi.org/10.1016/j.trsl.2011.10.012.CrossRefPubMed

18.

Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996;384(6608):458–60. https://doi.org/10.1038/384458a0.

19.

Tremblay M, Sanchez-Ferras O, Bouchard M. GATA transcription factors in development and disease. Development. 2018;145:dev164384.CrossRef

20.

D'Amato E, Giacopelli F, Giannattasio A, D'Annunzio G, Bocciardi R, Musso M, et al. Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis. Diabet Med. 2010;27(10):1195–200. https://doi.org/10.1111/j.1464-5491.2010.03046.x.CrossRefPubMed

21.

Huang WY, Heng HH, Liew CC. Assignment of the human GATA4 gene to 8p23.1-->p22 using fluorescence in situ hybridization analysis. Cytogenet Cell Genet. 1996;72(2-3):217–8. https://doi.org/10.1159/000134194.CrossRefPubMed

22.

Ohara Y, Atarashi T, Ishibashi T, Ohashi-Kobayashi A, Maeda M. GATA-4 gene organization and analysis of its promoter. Biol Pharm Bull. 2006;29(3):410–9. https://doi.org/10.1248/bpb.29.410.CrossRefPubMed

23.

Rojas A, Schachterle W, Xu SM, Martín F, Black BL. Direct transcriptional regulation of Gata4 during early endoderm specification is controlled by FoxA2 binding to an intronic enhancer. Dev Biol. 2010;346(2):346–55. https://doi.org/10.1016/j.ydbio.2010.07.032.CrossRefPubMedPubMedCentral

24.

Rojas A, Schachterle W, Xu SM, Black BL. An endoderm-specific transcriptional enhancer from the mouse Gata4 gene requires GATA and homeodomain protein-binding sites for function in vivo. Dev Dyn. 2009;238(10):2588–98. https://doi.org/10.1002/dvdy.22091.CrossRefPubMedPubMedCentral

25.

Donaghey J, Thakurela S, Charlton J, Chen JS, Smith ZD, Gu H, et al. Genetic determinants and epigenetic effects of pioneer-factor occupancy. Nat Genet. 2018;50(2):250–8. https://doi.org/10.1038/s41588-017-0034-3.

26.

Xuan S, Sussel L. GATA4 and GATA6 regulate pancreatic endoderm identity through inhibition of hedgehog signaling. Development. 2016;143(5):780–6. https://doi.org/10.1242/dev.127217.CrossRefPubMedPubMedCentral

27.

Iyer LM, Nagarajan S, Woelfer M, Schoger E, Khadjeh S, Zafiriou MP, et al. A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart. Nucleic Acids Res. 2018;46(6):2850–67. https://doi.org/10.1093/nar/gky049.

28.

Grant SFA. The TCF7L2 locus: a genetic window into the pathogenesis of type 1 and type 2 diabetes. Diabetes Care. 2019;42(9):1624–9. https://doi.org/10.2337/dci19-0001.CrossRefPubMedPubMedCentral

29.

Ritz-Laser B, Mamin A, Brun T, Avril I, Schwitzgebel VM, Philippe J. The zinc finger-containing transcription factor Gata-4 is expressed in the developing endocrine pancreas and activates glucagon gene expression. Mol Endocrinol. 2005;19(3):759–70. https://doi.org/10.1210/me.2004-0051.CrossRefPubMed

30.

Jepeal LI, Boylan MO, Michael WM. GATA-4 upregulates glucose-dependent insulinotropic polypeptide expression in cells of pancreatic and intestinal lineage. Mol Cell Endocrinol. 2008;287(1-2):20–9. https://doi.org/10.1016/j.mce.2008.01.024.CrossRefPubMedPubMedCentral

Title: Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus
Authors: Liangcai Ding
Mengdi Cai
Lu Chen
Han Yan
Shicheng Lu
Shuchao Pang
Bo Yan
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Diabetes
Type 2 Diabetes
Published in: BMC Endocrine Disorders / Issue 1/2021
Electronic ISSN: 1472-6823
DOI: https://doi.org/10.1186/s12902-021-00739-0

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Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus

Abstract

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Methods

Results

Conclusions

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Abstract

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