title: GATA factors promote ER integrity and β-cell survival and contribute to type 1 diabetes risk.
abstract: Pancreatic β-cell survival remains poorly understood despite decades of research. GATA transcription factors broadly regulate embryogenesis and influence survival of several cell types, but their role in adult β-cells remains undefined. To investigate the role of GATA factors in adult β-cells, we derived β-cell-inducible Gata4- and Gata6-knockout mice, along with whole-body inducible Gata4 knockouts. β-Cell Gata4 deletion modestly increased the proportion of dying β-cells in situ with ultrastructural abnormalities suggesting endoplasmic reticulum (ER) stress. Notably, glucose homeostasis was not grossly altered in Gata4- and Gata6-knockout mice, suggesting that GATA factors do not have essential roles in β-cells. Several ER stress signals were up-regulated in Gata4 and Gata6 knockouts, most notably CHOP, a known regulator of ER stress-induced apoptosis. However, ER stress signals were not elevated to levels observed after acute thapsigargin administration, suggesting that GATA deficiency only caused mild ER stress. Simultaneous deletion of Gata4 and CHOP partially restored β-cell survival. In contrast, whole-body inducible Gata4 knockouts displayed no evidence of ER stress in other GATA4-enriched tissues, such as heart. Indeed, distinct GATA transcriptional targets were differentially expressed in islets compared with heart. Such β-cell-specific findings prompted study of a large meta-analysis dataset to investigate single nucleotide polymorphisms harbored within the human GATA4 locus, revealing several variants significantly associated with type 1 diabetes mellitus. We conclude that GATA factors have important but nonessential roles to promote ER integrity and β-cell survival in a tissue-specific manner and that GATA factors likely contribute to type 1 diabetes mellitus pathogenesis.
authors.affiliation: Division of Endocrinology and Diabetes (D.J.S., C.J.W., S.Y.L., M.M.R., C.L.), Children's Hospital of Philadelphia, Department of Pediatrics (H.H., S.F.A.G.), Perelman School of Medicine, and Center for Applied Genomics (J.P.B., H.H., S.F.A.G.), Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Cardiology (W.T.P.), Children's Hospital, Boston, Harvard Medical School, Boston, Massachusetts 02115; Section of Pediatric Diabetes and Endocrinology (J.A.K.), Baylor College of Medicine, Houston, Texas 77030; and Diabetes and Endocrinology Service (J.A.K.), Texas Children's Hospital, Houston, Texas 77030.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sartori
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilbur
authors.forename: Simon Y
authors.initials: SY
authors.lastname: Long
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Rankin
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Jake A
authors.initials: JA
authors.lastname: Kushner
mesh_terms: D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D002470:Cell Survival; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000502:physiology*; D050991:GATA4 Transcription Factor / Q000502:physiology*; D050993:GATA6 Transcription Factor / Q000502:physiology; D005786:Gene Expression Regulation; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D051742:Transcription Factor CHOP / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497250:Ddit3 protein, mouse; D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C484171:Gata4 protein, mouse; C494760:Gata6 protein, mouse; D051742:Transcription Factor CHOP