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The Kru¨Ppel-Like Zinc Finger Protein Glis3 Directly and Indirectly

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The Kru¨Ppel-Like Zinc Finger Protein Glis3 Directly and Indirectly Published online 5 March 2009 Nucleic Acids Research, 2009, Vol. 37, No. 8 2529–2538 doi:10.1093/nar/gkp122 The Kru¨ ppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription Yisheng Yang1, Benny Hung-Junn Chang1, Susan L. Samson1, Ming V. Li1 and Lawrence Chan1,2,* 1Diabetes and Endocrinology Research Center, Division of Diabetes and Endocrinology, Department of Medicine and Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030 and 2St Luke’s Episcopal Hospital, Houston, TX, USA Downloaded from https://academic.oup.com/nar/article/37/8/2529/2410181 by guest on 27 September 2021 Received October 16, 2008; Revised February 13, 2009; Accepted February 14, 2009 ABSTRACT that they may function as positive and negative regulators of gene transcription. During embryonic development, Glis3 is a member of the Kru¨ ppel-like family of tran- Glis proteins are expressed in a spatially and temporally scription factors and is highly expressed in islet b specific manner, suggesting that they may play key roles cells. Mutations in GLIS3 cause the syndrome of in normal organogenesis. Glis1 is involved in the aber- neonatal diabetes and congenital hypothyroidism rant differentiation observed in psoriatic epidermis (1). (NDH). Our aim was to examine the role of Glis3 Glis2 is highly expressed in the kidney, and loss of Glis2 in b cells, specifically with regard to regulation of causes nephronophthisis in humans and mice through insulin gene transcription. We demonstrate that increased apoptosis and fibrosis (4,5). Glis2 has also insulin 2 (Ins2) mRNA expression in rat insulinoma been shown to be involved in the regulation of neuronal 832/13 cells is markedly increased by wild-type differentiation (2). Glis3 is highly expressed in the Glis3 overexpression, but not by the NDH1 mutant. metanephric mesenchyme during embryonic development Furthermore, expression of both Ins1 and Ins2 and in the uterus, pancreas and kidney of adult mice (3). It was also shown to bind to the promoter of fibroblast mRNA is downregulated when Glis3 is knocked growth factor 18 (FGF18) and promote osteoblast differ- down by siRNA. Glis3 binds to the Ins2 promoter entiation (6). in the cell, detected by chromatin immunoprecipi- In vitro assays indicate that all five ZF motifs appear tation. Deletion analysis of Ins2 promoter identifies essential for the binding of Glis3 to DNA, and the fourth a sequence (5’-GTCCCCTGCTGTGAA-3’) from À255 ZF is also involved in the nuclear localization of Glis3 to À241 as the Glis3 response element and binding (3,7). The C-terminal region of the protein contains a occur specifically via the Glis3 zinc finger region strong transactivation domain, and its deletion abolishes as revealed by mobility shift assays. Moreover, transcriptional activity. A recent report identified a Glis3 physically and functionally interacts with consensus binding site for Glis3 to be (G/C)TGGGGGG Pdx1, MafA and NeuroD1 to modulate Ins2 promoter T(A/C) using a DNA-binding site selection strategy that activity. Glis3 also may indirectly affect insulin combines PCR and electrophoretic mobility shift assays (EMSA) (7). However, this sequence was isolated by promoter activity through upregulation of MafA in vitro experiments and has not been identified in any and downregulation of Nkx6-1. This study uncovers endogenous Glis3 responsive promoters thus far. a role of Glis3 for regulation of insulin gene expres- Linkage analysis revealed that mutations in GLIS3 are sion and expands our understanding of its role in responsible for the syndrome of neonatal diabetes and the b cell. congenital hypothyroidism (NDH) (8). Glis3 mRNA is present in human and mouse pancreas from early devel- opmental stages through adulthood, with higher expres- INTRODUCTION sion in b cells than in other pancreatic islet or exocrine GLI and GLI-similar (Glis) transcription factors are cells (8). However, the functional role of Glis3 in b cells two closely related subfamilies of Kru¨ppel-like zinc has not been explored. Pancreatic islet development, b-cell finger (ZF) proteins (1–3). These factors contain five zinc maintenance and insulin gene transcription are dependent fingers in tandem for DNA binding. The Glis subfamily on multiple islet-enriched transcription factors, including is comprised of three members Glis1 to 3. Glis proteins Pdx1 (9–11), MafA (12–14), Pax6 (15,16) and BETA contain both repressor and activator domains, suggesting 2/NeuroD1 (17,18). Rat insulin promoter analyses have *To whom correspondence should be addressed. Tel: +1 713 798 4478; Fax: +1 713 798 8764; Email: [email protected] ß 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 2530 Nucleic Acids Research, 2009, Vol. 37, No. 8 localized binding of these factors to four promoter (24). We cultured NIH3T3 and BOSC23 cells (retrovirus regions, C2 (Pax6), A3 (Pdx1), C1 (MafA) and E1 packaging cell line) in DMEM with 10% FBS. CHO (BETA2/NeuroD1) (19,20). Other factors known to be cells were cultured in Ham’s F12 supplemented with involved in insulin gene transcription include Nkx6-1 10% FBS. and Pax4, both of which may have a repressive role. We used Lipofectamine 2000 (Invitrogen) for transfec- Study of these factors has provided insights into the tion according to the manufacturer’s instructions. Retro- machinery of insulin gene regulation and the pathogenesis virally transduced cells (22) were selected in a medium of diabetes. As Glis3 is highly expressed in pancreatic containing 1.0 mg/ml puromycin and 200 mg/ml hygromy- islets and mutations in GLIS3 cause neonatal diabetes cin B for 6–8 days. in humans (8,21), we hypothesized that this factor may For small interfering RNA (siRNA) experiments, regulate insulin gene expression. In this study, we found all control and Glis3 siRNAs were synthesized by that Glis3 binds to a cis-acting element (Glis3 response Dharmacon RNAi Technologies (Thermo Fisher Scienti- element, Glis3RE) in the rat insulin 2 promoter (RIP) fic). The rat Glis3 targeting siRNA sequences were: sense, Downloaded from https://academic.oup.com/nar/article/37/8/2529/2410181 by guest on 27 September 2021 and stimulates its transcription activity. Furthermore, 50-GCAUCAGUGUACGAUUUUU-30; antisense, 50-AA Glis3 interacts with b-cell-specific transcription factors— AUCGUACACUGUGAUGCUU-30. DharmaFECT Pdx1, MafA and NeuroD1—and can interact with these in siRNA transfection reagents were used for delivering a synergistic manner to increase insulin promoter activity. siRNA into target cells. The control siRNA is a non- In addition, Glis3 also regulates the expression of targeting siRNA (Dharmacon RNAi Technologies, a number of b cell transcription factors, such as MafA, D-001810-01-05). Nkx6-1 and Pax6. These findings constitute the first evidence that Glis3 regulates insulin gene expression in RNA isolation and quantitative polymerase chain pancreatic b cells. reaction (qPCR) Mouse tissues were dissected, snap frozen in liquid nitro- MATERIALS AND METHODS gen and stored at À808C until use. We isolated pancreatic islets from C57BL/6J mice as described previously (25). DNA constructs We used TRIZOL (Invitrogen, Carlsbad, CA) for RNA Using the known coding sequence of mouse Glis3 gene extraction and treated the RNA with amplification grade (Genbank accession number NM_175459), we constructed DNase I (Invitrogen) to remove genomic DNA contami- Glis3 cDNA and a Glis3 mutant cDNA (Glis3-NDH1) nation. Reverse transcription was performed with that corresponds to the sequence in a family with neonatal Superscript II reverse transcriptase kit (Invitrogen) using diabetes and congenital hypothyroidism (NDH1) syn- oligo dT. drome (8) by PCR mutagenesis, inserting a C nucleotide We performed qPCR using iQ SYBR Green Supermix at 2930 of wild-type Glis3. The mutant Glis3-NDH1 pro- (Bio-Rad Laboratories, Hercules, CA) with ROX as the tein terminates prematurely at aa 844 compared to the reference dye. The housekeeping gene Cyclophilin A was full-length protein of 935 aa. used as an internal control. Primer sequences are shown in The Glis3 cDNAs as well as control yellow fluorescent Supplementary Table S1. All primers span exons, except protein (YFP) were amplified by using PCR and cloned MafA, which has only one exon. Amplification was per- into the retroviral vector pSRQT (22). Additional con- formed using the Mx3000P Real-time PCR System structs were generated for transient transfection by using (Stratagene, La Jolla, CA) with the following parameters: a human elongation factor 1a (BOS) promoter-driven 958C for 30 s, 558C for 1 min, 728C for 30 s for 40 cycles. expression vector pBOS-MCS (23). SRa-Secreted The fidelity of the PCR products was confirmed by melt- Alkaline Phosphate (SEAP) construct was kindly pro- ing curve analysis and gel electrophoresis. vided by Dr David Spencer (Department of Immunology, Luciferase assay Baylor College of Medicine). The coding sequences of mouse Glis3, Glis3-NDH1, MafA, Pdx1 and NeuroD1 For transfection, we seeded cells in 24-well or 48-well cul- were ligated downstream of a c-myc tag. We constructed ture plates and collected the cultured media (Gluc and a luciferase (Luc) reporter by ligation downstream of the SEAP) or harvested the cells (Luc) 48 h later using Lysis rat insulin 2 promoter (RIP) from À696 to +8 into Buffer (Promega Corporation, Madison, WI). Luc assays pGL3-basic (Promega) or pGluc-basic (New England were performed with the Dual-Luciferase Kit (Promega) Biolabs) to generate RIP-Luc and RIP-Gluc constructs. or Gaussia Luciferase Assay Kit (New England Biolabs). Serial deletions of RIP were generated by PCR and sub- The results were normalized to the activity of the internal cloned into pGL3-basic.
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