Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic β-Cell Development and Insulin Gene Expression

Kang, Hong Soon; Kim, Yong Sik; ZeRuth, Gary; Beak, Ju Youn; Gerrish, Kevin; Kılıç, Gamze; Sosa–Pineda, Beatriz; Jensen, Jan; Pierreux, Christophe E.; Lemaigre, Frédéric P.; Foley, Julie F.; Jetten, Anton M.

doi:10.1128/mcb.00108-10

Cited by 21 publications

(39 citation statements)

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“…Two recent studies have shown that artificial mutations of this CCACC element lead to decreased INS promoter activity (36,42). Although previous studies failed to identify protein complexes interacting with this region in beta-cell nuclear extracts (17,36), a recent study showed that in vitro translated GLIS3, a zinc-finger transcription factor that is mutated in patients with neonatal diabetes and congenital hypothyroidism (43), exhibits sequence-specific binding to this region (42). Multiple DNA binding factors may 367_-344del (-129_-106) c. bind to CCACC elements in vitro, and thus future studies are warranted to determine if additional factors act through this element in vivo in beta cells.…”

Section: Discussionmentioning

confidence: 99%

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Garin

Edghill²,

Akerman³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

192

219

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Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. (8-12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).Insulin is secreted from islet beta cells of the pancreas. Insufficient secretion of insulin results in hyperglycemia and diabetes, whereas excessive secretion results in hypoglycemia. Insulin biosynthesis and secretion are therefore tightly regulated to maintain blood glucose levels within a narrow physiological range. Extensive studies have dissected an array of cis sequence elements in the INS promoter region and their cognate DNA binding factors, which together ensure the cellular specificity and rate of INS transcription (15)(16)(17)(18)(19)(20)(21)(22). In addition, insulin biosynthesis is strongly dependent on posttranscriptional regulatory mechanisms, including the modulation of translation and stability (23-25). The latter is largely mediated through sequences located in the untranslated regions of INS transcripts (26-28).

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Section: Discussionmentioning

confidence: 99%

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Garin

Edghill²,

Akerman³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

192

219

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“…The expression vectors 3xFlag-CMV10-ROR␣4 and 3xFlag-CMV10-Rev-Erb␣ were described previously (52). Reporter assays were performed in hepatoma Huh-7 cells as reported previously (25,52).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Kang¹,

Okamoto²,

Takeda³

et al. 2011

Physiological Genomics

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AM. Transcriptional profiling reveals a role for ROR␣ in regulating gene expression in obesity-associated inflammation and hepatic steatosis. Physiol Genomics 43: 818 -828, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00206.2010.-Retinoid-related orphan receptor (ROR)␣4 is the major ROR␣ isoform expressed in adipose tissues and liver. In this study we demonstrate that ROR␣-deficient staggerer mice (ROR␣ sg/sg ) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of ROR␣ sg/sg mice. In contrast, overexpression of ROR␣ in mouse hepatoma Hepa1-6 cells significantly increased the expression of genes that were repressed in ROR␣ sg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by ROR␣. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of ROR␣ sg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in ROR␣ sg/sg WAT. Moreover, ROR␣ sg/sg mice fed with an HFD were protected from the development of insulin resistance. ROR␣ sg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that ROR␣ plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, ROR␣ may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. staggerer mice; obesity; metabolic syndrome; macrophage; insulinresistance; diabetes; retinoid-related orphan receptors OBESITY IS A MAJOR GLOBAL health concern. In the United States alone, 30% of the general population is obese and an estimated 66% of all adults are overweight (40). Obesity is associated with an elevated risk of several pathologies, including Type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), cancer, and airway disease (18,36). The molecular links between obesity and these diseases are beginning to be understood. It is now well recognized that obesity is associated with chronic low-grade inflammation and that inflammatory processes play an important role in obesity and related pathologies (18,44,53). Infiltration of macrophages and various T-lymphocytes in hypertrophic adipose tissues have been considered as important early events in the development of obesity-associated complications (14, 38, 57) and the release of proinflammatory cytokines by adipose tissue plays a key ...

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“…Glis3 has also been shown to regulate insulin expression in mature b-cells. 201,[203][204][205] Glis3 binding sites were located near the distal promoter region of Ngn3 and Glis3 also interacts with Hnf6. 206 The Glis3/Hnf6 protein complex may operate in conjunction with a larger transcription factor network to regulate Ngn3 expression and thus activate endocrine cell specification.…”

Section: Gli-similar 3 (Glis3)mentioning

confidence: 98%

“…198,199 Glis3 knockout mice produce pups with neonatal diabetes presenting with hyperglycemia and hypoinsulinemia that die shortly after birth (Table 1). [200][201][202] These pups have diminished b-cells. Glis3 has also been shown to regulate insulin expression in mature b-cells.…”

Section: Gli-similar 3 (Glis3)mentioning

confidence: 99%

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Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

Dassaye

Naidoo

Cerf

2015

Islets

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Lineage tracing studies have revealed that transcription factors play a cardinal role in pancreatic development, differentiation and function. Three transitions define pancreatic organogenesis, differentiation and maturation. In the primary transition, when pancreatic organogenesis is initiated, there is active proliferation of pancreatic progenitor cells. During the secondary transition, defined by differentiation, there is growth, branching, differentiation and pancreatic cell lineage allocation. The tertiary transition is characterized by differentiated pancreatic cells that undergo further remodeling, including apoptosis, replication and neogenesis thereby establishing a mature organ. Transcription factors function at multiple levels and may regulate one another and auto-regulate. The interaction between extrinsic signals from non-pancreatic tissues and intrinsic transcription factors form a complex gene regulatory network ultimately culminating in the different cell lineages and tissue types in the developing pancreas. Mutations in these transcription factors clinically manifest as subtypes of diabetes mellitus. Current treatment for diabetes is not curative and thus, developmental biologists and stem cell researchers are utilizing knowledge of normal pancreatic development to explore novel therapeutic alternatives. This review summarizes current knowledge of transcription factors involved in pancreatic development and b-cell differentiation in rodents.

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Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic β-Cell Development and Insulin Gene Expression

Cited by 21 publications

References 0 publications

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis

Transcription factor regulation of pancreatic organogenesis, differentiation and maturation

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