Emerging Roles of GLIS3 in Neonatal Diabetes, Type 1 and Type 2 Diabetes

58 2

x wen and y yang GLIS3 and diabetes 58: 2 R73–R85 Review

Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

Xianjie Wen1,2 and Yisheng Yang1

1 Division of Endocrinology, Department of Medicine, MetroHealth Medical Center, Case Western Correspondence Reserve University, Cleveland, Ohio, USA should be addressed 2 Department of Anesthesiology, The First People’s Hospital of Foshan & Foshan Hospital of Sun Yat-sen to Y Yang University, Guangdong, China Email [email protected]

Abstract

GLI-similar 3 (GLIS3), a member of the Krüppel-like zinc finger protein subfamily, is Key Words predominantly expressed in the pancreas, thyroid and kidney. Glis3 mRNA can be ff GLIS3 initially detected in mouse pancreas at embryonic day 11.5 and is largely restricted ff neonatal diabetes to β cells, pancreatic polypeptide-expressing cells, as well as ductal cells at later stage ff type 1 diabetes of pancreas development. Mutations in GLIS3 cause a neonatal diabetes syndrome, ff type 2 diabetes characterized by neonatal diabetes, congenital hypothyroidism and polycystic kidney. ff insulin Importantly, genome-wide association studies showed that variations of GLIS3 are ff NGN3 strongly associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D) in multiple populations. GLIS3 cooperates with pancreatic and duodenal homeobox 1 (PDX1), v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA), as well as neurogenic differentiation 1 (NEUROD1) and potently controls insulin gene transcription. GLIS3 also plays a role in β cell survival and likely in insulin secretion. Any perturbation

Journal of Molecular Endocrinology of these functions may underlie all three forms of diabetes. GLIS3, synergistically with hepatocyte nuclear factor 6 (HNF6) and forkhead box A2 (FOXA2), controls fetal islet differentiation via transactivating neurogenin 3 (NGN3) and impairment of this function leads to neonatal diabetes. In addition, GLIS3 is also required for the compensatory β cell proliferation and mass expansion in response to insulin resistance, which if disrupted may predispose to T2D. The increasing understanding of the mechanisms of GLIS3 in β cell development, survival and function maintenance will provide new insights into disease Journal of Molecular pathogenesis and potential therapeutic target identification to combat diabetes. Endocrinology (2017) 58, R73–R85

Introduction

Type 1 (T1D) and type 2 diabetes (T2D) share some are found to be associated with T1D and T2D, respectively clinical and pathologic similarities, presenting with (Todd 2010, Bonnefond & Froguel 2015, Yang & Chan hyperglycemia resulting from islet β cell dysfunction and/ 2016). Remarkably, only a limited number of them or defect of insulin action. Hyperglycemia associated with are associated with both T1D and T2D. These include: both T1D and T2D may lead to similar chronic clinical insulin, GLI-similar 3 (GLIS3), RAS guanyl nucleotide- complications. However, genome-wide association studies releasing protein 1 (RASGRP1), cordon-bleu WH2 repeat (GWAS) indicate that their susceptibility loci are mostly protein (COBL), renalase and breast cancer anti-estrogen distinct. To date, more than 50 and 100 susceptibility loci resistance 1 (BCAR1) (Basile et al. 2014, Yang & Chan 2016).

10.1530/JME-16-0232 Journal of Molecular Endocrinology between rodentsandhuman. Apotentialbipartitenuclear to target DNA ( five ZFDs, and all of them are required for the binding molecular weight99.7 encodes aproteinof935amino acidswithacalculated of mouse and GLIS2,respectively( exhibits 93%and59%identitieswiththatinmouseGLIS1 Cys homologous zincfingerdomain(ZFD)consistingoffive finger proteins,suchasGLIS1–3.Theyshareahighly GLI-similar subfamilycontainsthreeKrüppel-likezinc Molecular characteristics ofGLIS3 in animalmodels. ( in monogenicneonataldiabetes( will focus on GLIS3 and diabetes, summarizing its roles in mice( is alsoinvolvedintheearlypostnatalspermatogenesis ( a criticalroleinmaintainingproperrenalfunctions containing transcriptionregulator1(WWTR1),plays GLIS3, interactingwithitsco-activatorWWdomain and metastaticmelanoma( ( ( ( inseveraltypesoftumors,suchasependymoma observed In addition,increasedexpressionofGLIS3hasbeen angleclosureglaucoma( with primary ( fluid tauandptau181,biomarkersforAlzheimer’s disease rs514716 is a risk variant for the levels of cerebrospinal thyroid-stimulating hormone( GLIS3 associated withanumberofotherdiseases.Forexample, GWAS havealsoidentifiedthatvariationsof ( 2006 hypothyroidism andpolycystickidney( syndrome characterizedbyneonataldiabetes,congenital 2003 to protein subfamily that was named due to its similarity & Chan2016 are theonlytwoknownmonogenicdiabetesgenes( Within thesesharedsusceptibilityloci,insulinand Table 2 Kang Yusenko &Kovacs2009 Cooper Lukashova-v Zangen Cruchaga Kang DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Review Drosophila 2 GLIS3 isamemberoftheKrüppel-likezincfinger /His ), whichcanbephenocopiedin ). Mutationsof rs1571583isassociatedwithelevatedserum et al t al et ), aswelltheunderlyingmechanismsexplored 2 et al -type zincfingermotifs.TheZFDinmouseGLIS3 Glis3 Kang . 2009 . 2009 t al et . 2010 ). regulatory proteinKrüppel( regulatory gene(NM_175459) contains 11exonsand t al et b . 2013 i. 1A Fig. , a Watanabe ). ArecentreportshowedthatGLIS3 ), chromophoberenalcellcarcinoma . 2016 et al GLIS3 kDa. Partofexon4encodes the ). ). The ZFDs are well conserved ). The ZFDs are well conserved ), breastcancer( Kim . 2007 GLIS3 a ). Inthepresentreview, we causeaneonataldiabetes et al Jayachandran et al Porcu ), proneuralglioblastoma rs736893isassociated x . 2009

yang Senee t al et et al et al Kim et al GLIS3 . 2016 ). . 2016 . 2011 . 2016 GLIS3 GLIS3 t al et t al et Yang are ). ). ). ) . .

GLIS3 proteinisoformsaandbhavebeendetermined. reported. However, onlytwomajorvariantsthatencode gene thatencodedifferentproteinisoformshavebeen harbors adistinct5 variant 1(NM_001042413),the2(NM_152629) These twovariantssharethelast9exons.Comparedto number ofalternativelysplicedvariantshuman the heart, liver and skeletal muscle ( contrast, thesmallertranscriptisstronglyexpressedin highly expressedinthepancreas,kidneyandthyroid; (0.8–2.0 transcripts ofhuman its C-terminus( that thetransactivationdomain(TAD) ofGLIS3residesat nucleus, but loses its transactivational activity, suggesting required. C-terminaltruncatedGLIS3canlocalizetothe putative NLS,whereasthefourthzincfingeriscompletely that thenuclearlocalizationofGLIS3doesnotrequire Interestingly, deletionandmutationanalysesrevealed and Lys661, whichoverlaps with thefifthzincfinger. localization signal(NLS)islocatedbetweenArg645 cells, involvesthesecretion of digestive enzymes thataid The exocrinepancreas,consisting ofacinarandductal The pancreashasbothexocrine andendocrinefunctions. GLIS3 inmousepancreas The temporal andspatial expression of β ( neurogenin 3( promoter/enhancer regionsofinsulin( CCCC(T/A)GCTGTGA(A/G), wasidentifiedinthe consensus GLIS3responseelement(GLIS3RE),G(T/C) GLIS3 ( TGGGGGGT(A/C) istheoptimalDNA-bindingsitefor contain 22 randomnucleotides. They reported that (G/C) (EMSA) toscreenamixtureof60 combined PCRandelectrophoretic mobility shiftassay specific bindingsiteforGLIS3,Beakandcoworkers signaling pathways ( suggesting across-talkbetweentheGLIS3andGLI may bind to the GLI consensus sequence GACCACCCAC, transactivator orrepressor. EarlystudyshowedthatGLIS3 contribute totheheterogeneitiesofclinicalpresentations. alternatively splicedvariantsofhuman in ashorterN-terminusisoformb( an in-frame portion of the 5 GLIS3 anddiabetes Ccnd2 cells. Published byBioscientifica Ltd. GLIS3 mayfunctionasacell-type-dependent RNA blothybridizationdetected two dominant ) ( Beak kb), inmultipletissues.The7.5 Yang t al et t al et Fig. 1A Ngn3 . 2008 ′ . 2013 untranslatedregion(UTR)andlacks ) ( GLIS3 Kim ) ( Yang ). Subsequently, an endogenous Beak Downloaded fromBioscientifica.com at09/30/202101:03:31AM ) inisletprogenitorsoradult gene,long(7.5 t al et t al et et al ′ coding region, resulting . 2003 bp oligonucleotidesthat . 2008 . 2011 Senee 58 ). To identifythe Yang ). : 2 ) andcyclind2 GLIS3 i. 1B Fig. kb transcriptis kb) andsmaller et al et al genemay . 2006 ). These . 2009 GLIS3 R74 ). A via freeaccess ),

Review x wen and y yang GLIS3 and diabetes 58:2 R75

Table 1 Clinical characteristics of neonatal diabetes syndrome in patients with GLIS3 mutation.

Family/ Mutation Ethnicity patient NDM CH PKD Other features Alive/dead Reference p.625fs703Stopa Arabia 1/3 Y Y Yb Liver fibrosis, IUGR, facial Died at 10 d, 6 Senee et al. (2006) dysmorphism, congenital and glaucoma 16 months p.Cys536Trp Arabia 1/1 Y N N IUGR, hyperactivity Alive Dimitri et al. (2015) (6.8 years) p.Gly311Alafs Pakistani 1/1 Y Y Y Right sensorineural deafness, Alive Dimitri et al. (2015) skeletal disease (2.5 years) p.His561Tyr Kurds 1/1 Y Y Y Liver fibrosis, facial dysmorphism, Alive Dimitri et al. (2015) congenital glaucoma, patent (4.5 years) ductus arteriosus p.Arg589Trp/ Caucasian 1/1 Y N N IUGR, choanal atresia, hiatus Alive Dimitri et al. (2015) exons 1–11 delc hernia (36 years) 426 kb deletion Arabia 1/1 Y Y N IUGR, congenital glaucoma Alive (2 years) Senee et al. (2006) Chr9:4176077– 4601776 149 kb deletion French 1/2 Y Y N IUGR Alive (14 and Senee et al. (2006) Chr9:4249915– 22 years) 4398572 Exons 1–2 Arabia 2/2 Y Y Y Insulin resistance or high insulin Alive (6 years Dimitri et al. (2015) deletion sensitivity, ostium secundum and atrial, septal defect, facial 7 months) dysmorphism, congenital glaucoma Exons 1–4 Caucasian 1/2 Y Y Y Exocrine insufficiency, liver Alive (6 years Dimitri et al. (2011, deletion fibrosis, IUGR, bilateral and 2015) sensorineural deafness, facial 20 months) dysmorphism, pancreatic cyst Exons 3–4 Turkish 1/1 Y Y Y IUGR, liver fibrosis, facial Died at Dimitri et al. (2015) deletion dysmorphism 6 months Exons 5–9 Arabia 1/1 Y Y Y IUGR, liver fibrosis, facial Alive Dimitri et al. (2015) deletion dysmorphism (4.7 years) Exons 9–11 African– 1/1 Y Y Y IUGR, liver fibrosis, facial Died at Dimitri et al. (2015) deletion American dysmorphism, skeletal disease, 6 years congenital glaucoma Journal of Molecular Endocrinology Exons 10–11 Yemeni 1/1 Y Y Y IUGR, liver fibrosis, exocrine Alive (3 years) Dimitri et al. (2015) deletion insufficiency, facial dysmorphism, congenital glaucoma p.Phe857Tyrc,d Chinese 1/1 Y N N/A Liver and kidney failure Died at Cao et al. (2016) 1.5 years

aEqual to p.779fs858Stop in the updated version of human GLIS3 gene (NM_001042413); bthe patient who died at 10 day of age did not present PKD; cindicates heterozygous mutation. All others are homozygous mutations in GLIS3; dit is unclear if this mutation was causative; whether this patient developed PKD was not documented, although we note that the patient died of liver and kidney failure. CH, congenital hypothyroidism; IUGR, intrauterine growth restriction; NDM, neonatal diabetes mellitus; N, no; PKD, polycystic kidney disease; Y, yes.

nutrient digestion. The endocrine pancreas (also called pancreas development contains a primary transition from islet), containing five types of hormone-expressing cells E9.5 to E12.5 and a secondary transition from E12.5 to such as α, β, δ, ε and pancreatic polypeptide (PP), that birth. During the primary transition, a subset of progenitor is responsible for the regulation of glucose homeostasis. cells initiate the expression of NGN3, which marks the Both pancreatic exocrine and endocrine cells arise from a onset of endocrine cell differentiation, whereas the common origin of progenitor cells in the gut endoderm. subset of trunk epithelial cells that do not express NGN3 Pancreas specification becomes morphologically evident develop into ductal cells. During the secondary transition, around embryonic day (E) 8.5–E9.0 with the expression of endocrine hormone-expressing cells are rapidly expanded pancreatic and duodenal homeobox 1 (PDX1). Pancreatic in the developing pancreas starting from E13.5 (Oliver- progenitors adopt either tip identity that develops to an Krasinski & Stoffers 2008, Shih et al. 2013). acinar phenotype or trunk identity that is bipotential for GLIS3 is predominantly expressed in the pancreas, the ductal and endocrine cell fate (Shih et al. 2013). Mouse thyroid and kidney, with modest expression in the heart,

DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Table 2 Variations of GLIS3 associated with common T1D and T2D. Review

Study type Sample size Ethnicity Major findings Effect size* Reference Variations of GLIS3 and T1D GWAS/meta-analysis 7514 cases/9045 controls European GLIS3 rs7020673 associated with T1D 0.88, 0.97 Barrett et al. (2009) GWAS 858 general population children/851 Non-Hispanic White GLIS3 rs7020673 associated with the 0.77a Steck et al. (2014) first-degree relatives of T1D patients development of islet autoimmunity GWAS 4574 cases/1207 controls, validated in T1D genetics GLIS3 rs7020673 contributes to the N/A Winkler et al. 765 cases/423 controls consortium, Germans prediction of T1D (2014) GWAS replication analysis 23 cases/39 controls (related Pakistani GLIS3 rs7020673 associated with T1D N/A Kiani et al. (2015) individuals); 68 cases/61 controls (unrelated individuals) GWAS 706 cases/863 controls Japanese GLIS3 A908V associated with resistance 0.046b Awata et al. (2013)

to T1D x

wen

© 2017SocietyforEndocrinology Variations of GLIS3 and T2D c GWAS meta-analysis 46,186 non-diabetic participants and European GLIS3 rs7034200 associated with fasting 0.018 Dupuis et al. (2010) and follow-up in 76,558 additional glucose and impaired β cell function Printed inGreatBritain subjects y

−0.02d yang GWAS 6784 middle-aged participants Danish GLIS3 rs7034200 associated with reduced −0.031c Boesgaard et al. glucose-stimulated β cell function (2010) GWAS replication analysis 3410 T2D patients and 3412 controls Chinese GLIS3 rs7034200 associated with T2D 1.103 Hu et al. (2010) GWAS meta-analysis Over 6000 healthy children and European and GLIS3 rs7034200 associated with impaired −0.023d Barker et al. (2011) adolescents Australians β cell function and altered fasting glucose

GWAS 1678 cases/1584 controls South Asians GLIS3 rs7034200 associated with T2D 1.03 Rees et al. (2011) GLIS3 anddiabetes Published byBioscientifica Ltd. GWAS 3210 unrelated individuals Chinese Han GLIS3 rs7034200 associated with fasting 1.27 Liu et al. (2011) glucose, β cell function and T2D GWAS meta-analysis, Meta-analysis: 6952 cases/11,865 East Asians GLIS3 rs7041847 associated with T2D 1.1 Cho et al. (2012) replication analysis controls; in silico replication: 5843 cases/4,574 controls; de novo replication: 12,284 cases/13,172 controls GWAS 2632 cases/2050 controls Japanese GLIS3 rs7034200 borderline associated 1.09 Fujita et al. (2012) with T2D GWAS replication analysis 3548 DPP participants Multiple ethnics No impact of GLIS3 rs7034200 on N/A Florez et al. (2012) Downloaded fromBioscientifica.com at09/30/202101:03:31AM diabetes incidence or interaction with preventive interventions GWAS meta-analysis 1329 participants in 329 families Hispanic-American GLIS3 rs2380949 associated with insulin N/A Goodarzi et al. clearance (2013) GWAS replication analysis 5315 cases/2064 controls Japanese GLIS3 rs7041847 confers susceptibility to 1.03 Sakai et al. (2013)

T2D 58

GWAS 8569 cases/8923 controls Chinese Han, East GLIS3 rs10814916 associated with the risk 1.11 Li et al. (2013) : 2 Asians of T2D GWAS meta-analysis 5974 non-diabetic subjects Koreans GLIS3 rs7034200 associated with impaired −0.02d Hong et al. (2014) β cell function Matched case-control 160 T2D/160 controls, 195 impaired Chinese Han GLIS3 rs7034200 associated with the risk 1.625 Dou et al. (2016)

glucose regulation/195 controls of T2D R76 via freeaccess *Effect size is presented as odds ratio unless specified;a hazard ratio; bHaldane’s odds ratio; cper-allele effect; dβ-coefficient. N/A, not available. Review x wen and y yang GLIS3 and diabetes 58:2 R77

Figure 1 Schematic diagrams of mouse and human GLIS3 gene and protein structures. (A) Mouse Glis3 gene and protein structures. The full-length mouse Glis3 gene contains 11 exons and encodes a protein of 935 aa. The ZFD is encoded by part of exon 4 and is responsible for the binding to the consensus GLIS3RE of its target genes such as insulin, Ngn3 and Ccnd2. TAD is localized at its C-terminus. CUL3 and ITCH promote GLIS3 polyubiquitination and degradation via the proteasomal pathway. SUFU, interacting with GLIS3 through the conserved VYGHF motif at N-terminus of GLIS3, was shown to inhibit the association of CUL3 with GLIS3, thereby protecting GLIS3 protein from proteolytic degradation. (B) Human GLIS3 gene and protein structures. Human GLIS3 gene have two major variants that encode GLIS3 protein isoforms a and b that share the last 9 exons. The variant 1 encodes the longest isoform a with 930 aa. The variant 2 harbors a distinct 5′ UTR and lacks an in-frame portion of the 5′ coding region, resulting in a shorter N-terminus in isoform b with 775 aa, compared to variant 1. Journal of Molecular Endocrinology lung, brain, liver, skeletal muscle and testis (Kim et al. was drastically reduced at both mRNA and protein levels 2003, Senee et al. 2006, Yang et al. 2009). RT-PCR and at E12.5, which reveals that Glis3 gene is functionally in situ hybridization showed that Glis3 mRNA can be important in mouse endocrine pancreas development initially detected at E11.5 and significantly increases at at early as E12.5, immediately before the secondary E12.5 in mouse pancreata (Kang et al. 2009b). Recently, transition begins (Yang et al. 2011). Jetten and coworkers generated a GLIS3-enhanced green In the GLIS3-EGFP knock-in mice, GLIS3-EGFP fluorescent protein (EGFP) knock-in mouse model and mainly co-expresses with PDX1 and sex-determining reported that GLIS3 protein was undetectable during region Y-box 9 (SOX9) in the trunk domains, but not the primary transition (E10.5–12.5), instead it was first in the tip domains at E13.5. This is consistent with the detected at E13.5 in the nucleus of bipotent progenitors observation that GLIS3 is predominantly expressed in of the pancreas development (Kang et al. 2016b). Several endocrine and preductal progenitors (Kang et al. 2016b). possibilities might explain this discrepancy in the At later stages, GLIS3 is largely restricted to β cells and expression of GLIS3 mRNA and protein. These include PP-expressing cells, as well as ductal cells. GLIS3 protein delayed protein synthesis and accumulation due to is also detected in a few δ cells, but neither in α and ε post-transcriptional regulation and GLIS3 protein may cells nor in acinar cells (Kang et al. 2016b), which is in be unstable in the pancreata between E11.5 and E12.5. agreement with the reports that exocrine pancreas was However, distinct sensitivity of the approaches used in unaffected in Glis3-deficient mice (Kang et al. 2009b, these experiments could more likely lead to this apparent Watanabe et al. 2009, Yang et al. 2011). We, however, difference. In Glis3-deficient mouse pancreas, the note that some patients with GLIS3 mutations present expression of NGN3, a direct downstream target of GLIS3, exocrine pancreas insufficiency Table ( 1). The reason

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0232 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:03:31AM via free access Journal of Molecular Endocrinology syndrome inaconsanguineous SaudiArabianfamily In 2003,Taha andcoworkersfirstdescribedarareclinical GLIS3 andneonatal diabetes syndrome the isletsfromT2Ddonors( diabetes astheexpressionof GLIS3 however, remains tobedeterminedwhether targetof regulatory knockdown human of lncRNA functions ( are usuallylineagespecificandregulatemultiplebiological coding transcriptslongerthan200nucleotides.LncRNAs targets includinginsulin( GLIS3, resultinginthereducedexpressionofdownstream GLIS3 proteinturnovertoinhibitthetransactivationof to reducetheGLIS3stability. ITCHsignificantlyincreased of GLIS3andenhancedproteasomaldegradation the WW domainswith a ubiquitin protein ligase, interacted with GLIS3 through further reportedthattheITCHprotein,anitchyE3 andyeasttwo-hybrid analysis, they mass spectrometry stability ofGLIS3protein( protein fromproteolyticdegradationandenhancingthe association ofCUL3withGLIS3,therebyprotectingGLIS3 proteasomal pathway. SUFUwasshowntoinhibitthe GLIS3 polyubiquitinationanddegradationviathe26S ligase scaffoldingproteinCullin3(CUL3)promotes ( activation oftheinsulinpromotermediatedbyGLIS3 Functional studyshowedthattheSUFUrepressed VYGHFmotifatN-terminusofGLIS3. the conserved that theSUFUwasabletointeractwithGLIS3through Subsequently, co-immunoprecipitationassayconfirmed and based transcriptome and chromatinmaps of human islets regulator ofhedgehogsignaling( fused homolog(SUFU),atumorsuppressorandnegative suggested that GLIS3 may interact with suppressor of A previoushigh-throughputyeasttwo-hybridscreening Interacting partnersofGLIS3 species difference. for thisdiscrepancyremainsunclearandlikelydueto ZeRuth DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Review GLIS3 Long non-codingRNAs(lncRNAs)arenon-protein Combining gel-enhancedliquidchromatography β cells,Ferrerandcoworkersidentifieda regulation correlates with the pathophysiology of HI-LNC25 wassignificantlyreducedinthe t al et Knoll . 2011 et al . TheyfoundthatthemRNAexpression β HI-LNC25 . 2015 ). Inaddition,theE3ubiquitin cells,suggestingthat PPxY ZeRuth Fig. 1A ). Inanintegratedsequence- Moran HI-LNC25 motif located at N-terminus ( x ) ( Moran et al

et al yang t al et ). β cell-specific ). . 2012 GLIS3 HI-LNC25 HI-LNC25 . 2011 . 2005 isa ). It, ). ). - - splenic cyst,choanalatresia,sensorineuraldeafness craniosynostosis, hiatushernia,atrialseptaldefect, a broadspectrumofclinicalphenotypes.Theseinclude hypothyroidism andpolycystickidneys,theypresented or mutations.Inadditiontoneonataldiabetes,congenital homozygous orcompoundpartial coworkers reportedadditionalpatientswhocarried other families( deletions affectingthe5 harbor homozygouslargefragment(426and149 In addition,theyreportedthataffectedindividuals underlies theneonataldiabetessyndromeinonefamily. a homozygousinsertion(2067insC)in monthsoflife,respectively( 6 and16 hepatic fibrosis.Threeaffectedchildrendiedat10 days, retardation, facial anomalies, congenital glaucoma and hypothyroidism, polycystickidneys,intrauterinegrowth characterized bypermanentneonataldiabetes,congenital and exocrinepancreaticinsufficiency( Senee compound heterozygousmutations (p.Arg589Trp/exons decay ( expression asaresultof nonsense-mediatedmRNA ( truncated proteinthatcompletely lossesitstransactivities (2067insC) in phenotypes. Forexample,ahomozygousinsertion function of ( which maycontribute to the variability in phenotype multiple transcriptswithdifferentialexpressionprofiles, are summarizedin associated withthemutations in for thistypeofneonataldiabetes.Theclinicalfeatures insulin therapyshouldbestartedwithcarefulattention high insulinsensitivity( deletion in For example,thepatientswithhomozygousexons1–2 insulin sensitivitythatisnotassociatedwithgenotypes. patients presentwithneonataldiabetes,butvariable toadulthood.Interestingly,or renalcysts,survived all neonatal diabetes,butnotcongenitalhypothyroidism GLIS3 patient with compound heterozygous mutations in lip insomepatients( long philtrum with a thin vermilion border of the upper elongated andupslantedpalpebralfissures,persistent including bilaterallow-setears,depressednasalbridge, 2011 GLIS3 anddiabetes Senee Senee Published byBioscientifica Ltd. As stated previously, human , (p.Arg589Trp/exons 1–11 del) presenting with et al 2015 et al et al Lykke-Andersen &Jensen2015 . 2006 ). Theyfurtherdescribedfacialdysmorphism . 2006 . 2006 GLIS3 GLIS3 GLIS3 Senee ). In2006,Senéeandcoworkersidentified maypresentwithinsulinresistanceor ). Inaddition,theseverityofimpaired , mutantsmayalsocausethevariable Table 1 Yang leadstoeitheraframeshiftand t al et Dimitri Downloaded fromBioscientifica.com at09/30/202101:03:31AM ′ et al UTRofthe Dimitri . . 2006 . 2009 t al et ). Recently, Dimitriand GLIS3 t al et . 2016 ) orlikelynoprotein GLIS3 58 . 2015 GLIS3 GLIS3 identifiedtodate Taha : 2 ), whereasthe genedeletions ). Notably, one Dimitri geneintwo ). Therefore, gene has GLIS3 t al et . 2003 that t al et R78 kb) via freeaccess . , Journal of Molecular Endocrinology frequency ( (IA) andfailedtopredicttheprogressionfromIAT1D association withthedevelopmentofisletautoimmunity However, to thatprovidedbyHLAalone( improved thepredictionaccuracyofT1D,compared of associated withT1D.Theyfoundthatthecombination 40 non-HLAgenesinglenucleotidepolymorphisms(SNP) Winkler andcoworkersassessedthepredictive powerof of thegeneticriskthisdisease( susceptibility locusforT1D,withanestimated30–50% patients ( This associationwasreplicatedrecentlyinPakistaniT1D harbors only a single gene, strong linkagedisequilibriumatchromosome9p24.2that in European populations. They found that the region of between a Barrett andcoworkersfirstidentifiedtheassociation susceptibility forcommonT1D( the humangenomehavebeenidentifiedtoconfer factors ( the actionofacombinationgeneticandenvironmental Common T1D is an autoimmune disorder that arises from GLIS3 andtype1diabetes ( 1–11 del)mightpartiallyaffectthefunctionofGLIS3 index (BMI),bloodpressure or lipidprofileinparticipants glucose in T2D trait, but not associated with body mass one ofninenewlyidentified lociassociatedwithfasting coworkers first identified the strongly associatedwithcommonT1D,Dupuisand Shortly afterthereportthat GLIS3 andtype2diabetes disprove thishypothesis. Additional functionalstudiesareneededtoprove or tolerance thanwild-type more efficientlyinducecentralorperipheralimmune proposed thattheprotectivevariant is alsomoderatelyexpressedinhumanthymus,they mechanism remains elusive. Given that resistance toT1DinJapanesepopulation.Theunderlying Steck Dimitri http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0232 Review GLIS3 Interestingly, Awata andcoworkers reportedthatlow The humanleukocyteantigen(HLA)isthemajor et al Herold et al rs7020673andothereightSNPssignificantly Kiani . 2014 GLIS3 GLIS3 GLIS3 . 2015 et al A908Vvariantwasassociatedwiththe ). t al et rs7020673 alone exhibited nominal variant rs7020673 and common T1D . 2015 ). . 2013 ). GLIS3 ). Morethan50regionsof GLIS3 GLIS3 908A( x

variantwas yang GLIS3 908Vmight t al et t al et t al et et al . 2014 . 1996 . 2009 mRNA . 2013 ). ). ). ). ). Furthermore, the glucose-raising allele of Europeandescent( diabetes intheDiabetesPreventionProgram( lifestyle modificationsinindividualsathighriskof suchasmetforminor with preventiveinterventions significant impactondiabetesincidenceorinteraction with otherpreviously identified T2Driskloci, hadno is worthmentioningthat differences inglucoselevelsfromchildhoodonward.It age-independent effect ofthislocusoninter-individual and adolescents( 2010 function bothinnon-diabeticadults( A wasalsostronglyassociatedwithimpaired with T2DinaJapanesepopulation( Asians ( ( been replicatedinDanes( 2012 targets ofGLIS3,suchasNGN3 ( Yang different strategies( independently generated insight into the role of GLIS3 in diabetes, three groups β mechanisms werelargelyunknownuntil diabetes inpeopleareintriguing.However, theunderlying These associationstudiesbetween association between GLIS3anddiabetes The molecularmechanismsthat underliethe traits aresummarizedin clearance. play adualroleinregulatingbothinsulinproductionand ( associated withinsulinclearanceinHispanicAmericans those inEuropeans. higher rates of T2D at lower average BMI, compared to the uniqueepidemiccharacteristicsinEastAsians,e.g., address whether susceptibility onlyinEastAsians.Itwouldbeofinterestto populations, to and inChinese( to T2D in East Asians ( rs10814916, werereportedtoconferthesusceptibility GLIS3 anddiabetes Hu Goodarzi cell-specificknockoutmiceweregenerated. To gain Published byBioscientifica Ltd. GLIS3 In addition, two other Notably, et al , ). et al Hong Rees . 2010 rs7034200,ariskSNPforT2Dinmulti-ethnic . 2011 GLIS3 t al et t al et t al et GLIS3 , GLIS3 . 2013 Liu ) andidentifiedthreedirect downstream variantsassociatedwithT2Dandrelated GLIS3 Li . 2014 Barker . 2011 Kang et al rs7041847,appearstoconferT2D t al et rs2380949wasfoundtobe Dupuis ), whichsuggeststhatGLIS3may rs7041847contributestounderlie Cho . 2011 ) aswellinhealthychildren . 2013 Downloaded fromBioscientifica.com at09/30/202101:03:31AM ), withaborderlineassociation Table 2 et al t al et Boesgaard GLIS3 GLIS3 et al . 2009 Glis3 et al , . 2011 Dou ), respectively. Incontrast . . 2012 Yang rs7034200,incommon variants, rs7041847 and . 2010 -deficient mice with b et al , ), whichsuggestsan Watanabe et al GLIS3 58 et al Fujita , ). Thisfindinghas . 2016 : Sakai GLIS3 2 . 2010 Glis3 . 2011 Dupuis variantsand t al et ) andSouth Florez rs7034200 et al globaland et al ), Chinese ), insulin . 2012 . 2013 . 2009 t al et R79 β et al -cell via freeaccess ). ) . . , Journal of Molecular Endocrinology transcription factor( Ngn3 HNF6 aswellFOXA2and synergisticallytransactivated further reportedthatGLIS3 physicallyinteractedwith pancreata.They immunoprecipitation inembryonic its transcription,whichwasconfirmedbychromatin bound tothepromoter/enhancerof and EMSA,Yang andcoworkersfoundthatGLIS3directly ductal cells.Combining the significantly upregulatedthe to thatin Glis3 pancreataof was drasticallyreducedintheembryonic in thedevelopingpancreas.TheexpressionofNGN3 1 FOXA2 ( HNF6 ( ( number ofpositiveregulatorsNGN3,suchasPDX1 development wasunaffected( hypothyroidism andpolycystickidney, whereasexocrine Glis3 of endocrine cells weremarkedlyreducedintheneonatal Immunostaining indicatedthatthenumbersofalltypes organized morphologicallyintheneonatal the sizeofisletswasmuchsmallerandwerepoorly only ~15%ofthatin 2011 of life( hyperglycemia andketoacidosiswithinthefirstfewdays 2006 syndrome inpatientswith Recapitulating thephenotypeofneonataldiabetes transactivating GLIS3 isrequired forproper isletdifferentiation by of adult for fetalisletdifferentiationbutalsothemaintenance cells. These studies reveal that GLIS3 is required not only ( ( endocrine cellfate determination ( 2016 protein wasundetectableinmouseacinarcells( 2011 Miyazaki Yang Yang β DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Review (HNF1 Proper NGN3 expression is crucial for pancreatic ). Thetotalisletareaof ), b ), whichissupportedbytherecentreportthatGLIS3 − −/− ( / ). − et al t al et Yang micebothatmRNAandproteinlevels,compared mice( Kang Jacquemin Glis3 β Lee cellfunction. β . 2009 ) ( . 2013 t al et Glis3 -deficient ( t al et et al t al et Maestro Yang Ngn3 . 2004 +/+ . 2009 , . 2011 2013 ), inthepancreaticprogenitorsand . 2001 mice,whereasGLIS3overexpression et al et al Shih t al et b . 2000 , ), theendocrinelineage-defining , . 2011 , Glis3 ) andhepatocytenuclearfactor ZeRuth Watanabe et al Glis3 Oliver-Krasinski . 2003 GLIS3 in vitro −/− Kang ), SOX9( . 2013 ). Themicealsodeveloped Glis3 Ngn3 +/+ ) micediedwithsevere et al x littermates.Moreover, mutations(

) havebeenidentified wen luciferasereportassay © 2017SocietyforEndocrinology et al − mRNAinpancreatic et al ). / − Shih . 2013 neonatalmicewas and Ngn3 . 2009 Lynn . 2009 Printed inGreatBritain y t al et andactivated

) andCCND2 yang t al et Glis3 b et al , Senee , . 2013 Kang Yang Yang . 2009 − . 2007 / − mice. et al et al et al et al ). A ), ), β . . . .

of insulinsecretion 80% ( insulin productionismarkedly reducedbymorethan play aroleininsulinsecretion in controlling insulingenetranscription, GLIS3mayalso Chan 2016 to thesulfonylureaclassofantidiabeticdrugs( ATP andADPtoinitiateinsulinsecretioninresponse SUR1 isasensorofintracellularlevelsthenucleotides to thatintheirwild-typelittermates( pancreata of sulfonylurea receptor 1 (SUR1) was also decreased in the transporter sub-familyCmember8( In addition,themRNAexpressionofATP-binding cassette compared tothatinthecontrolmice( reduced inadultisletsof ( the insulingene. data demonstratedthatGLIS3isapotenttransactivatorof 2013 that mutations in the GLIS3RE markedly attenuated the transcription ( PDX1, MAFA andNEUROD1tocontrolinsulingene that GLIS3physicallyandfunctionallyinteractswith a GLIS3REintheinsulingenepromoterandfound the expressionof of stable overexpressionofGLIS3enhanced the expression Early studiesinratinsulinoma832/13 cells revealedthat elements and E boxes, respectively ( gene transcriptionthroughtheirbindingtoAboxes,C For example,PDX1,MAFA andNEUROD1controlinsulin confer the transcriptional control of insulin expression. ubiquitous transcriptionfactors,havebeenidentifiedto promoter region, which bind the key sequencesintheinsulin A numberofcis-actingregulatory GLIS3 controls insulingenetranscription death ( insulin expression,leadingtofulminantdiabetesand inactivation of coworkers foundthattamoxifen-mediated interaction of its partners with the promoter ( of GLIS3totheinsulinpromoterisrequiredfor MAFA andNEUROD1,indicatingthatthedirectbinding insulin promoteractivationbyacombinationofPDX1, GLIS3 anddiabetes Glut2 Published byBioscientifica Ltd. Ins2 Interestingly, themRNAlevelofglucosetransporter2 ). Inagreementwiththese Yang ), thekey , whereasknockdownofGLIS3drasticallyreduced Yang et al ). Thesedatasuggestedthatinadditionto t al et Glis3 Yang . 2011 β Glis3 cellglucosetransporter, wassignificantly . 2013 − Ins1 / et al − per se miceatpostnatalday3,compared ), itisachallengetoassessthe defect in mice markedly downregulates and . 2009 ). Thus, both β Downloaded fromBioscientifica.com at09/30/202101:03:31AM in cell-specific Glis3 Ins2 ). Subsequentstudyshowed in vitro . Theyfurtheridentified − / − Hay & Docherty 2006 β mice. cells.Giventhatthe Glis3 58 in vitro findings, Yang and Kang β Yang cell-restricted or : Abcc8 2 -deficient mice, β et al cell-specific ZeRuth and et al ) encoding . 2009 . 2013 Yang & in vivo R80 et al b via freeaccess ). ). ). .

Review x wen and y yang GLIS3 and diabetes 58:2 R81

GLIS3 is required for obesity-induced β cell proliferation identified that the variant rs11063069 G inCCND2 and mass expansion confers susceptibility to T2D (Morris et al. 2012), whereas the variant rs76895963 G in CCND2 reduces risk of In states of insulin resistance, such as obesity and T2D by half and is correlated with increased CCND2 pregnancy, the expansion of β cell mass in accordance expression (Steinthorsdottir et al. 2014). Further research with the requirements for insulin is critical for is needed to identify additional potential targets of GLIS3 maintaining glucose homeostasis and preventing to fully elucidate the molecular mechanisms that underlie diabetes. Increasing β cell proliferation is the primary reduced GLIS3 and defective β cell mass expansion. mechanism underlying this β cell mass expansion, although neogenesis may also be involved (Ackermann & Gannon 2007). Failure of β cell mass expansion may GLIS3 may protect pancreatic β cells against apoptosis be associated with T2D. Consistent with an autosomal recessive inheritance observed in humans, heterozygous The loss of β cell mass is a critical feature for both T1D Glis3-mutant (Glis3+/−) mice remained euglycemic and T2D. Pro-inflammatory cytokines, such as interleukin while on a regular chow diet. However, when they 1β (IL1β) and interferon γ (IFNγ), and the saturated were challenged with a high-fat diet (HFD), adult nonesterified fatty acid palmitate, may contribute to the mice developed overt diabetes with hypoinsulinemia. β cell loss in T1D and T2D, respectively (Donath et al. Histology showed that Glis3+/− mice failed β cell mass 2005, Santin & Eizirik 2013). An in vitro study showed expansion in response to HFD. Mechanistically, it has that Glis3 knockdown in INS-1 cells increased basal and been shown that GLIS3 controls β cell proliferation in inflammatory cytokine (IL1β + IFNγ)- or palmitate-induced response to HFD feeding partly by direct regulation of β cell apoptosis. Reduced GLIS3 expression was found to Ccnd2 mRNA transcription (Yang et al. 2013). modulate the alternative splicing of the pro-apoptotic CCND2 is essential for postnatal pancreatic β cell BH3-only protein Bim, promoting the expression of the growth (Georgia & Bhushan 2004, Kushner et al. 2005) pro-death variant BimS and β cell death (Nogueira et al. and compensatory mass expansion in response to insulin 2013). These data suggest that proper GLIS3 expression resistance (Georgia et al. 2010). Interestingly, GWAS could be required for β cell survival. This notion was Journal of Molecular Endocrinology

Figure 2 Current understanding of the molecular actions of GLIS3 in diabetes. This figure summarizes the pathways by which ablation, loss-of-function mutations or functional impairment of GLIS3 cause neonatal diabetes, as well as common T1D and T2D. See text for details. A full colour version of this figure is available athttp://dx.doi. org/10.1530/JME-16-0232.

http://jme.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0232 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:03:31AM via free access Journal of Molecular Endocrinology insulin, leadingtovariablephenotypes ( largely determinestheexpression levelsofNGN3and unveiled thatthedifferential genedosageofGLIS3 neonatal diabetes( insulin productionatbirth, culminatinginpermanent β downstream targetNGN3,causingseverelyabnormal proper expressionand/orfunctionofGLIS3anditsdirect of diabetes.Mutationsordeletionsin 2016 and insulin secretion( ( ( GLIS3 mechanistic basisforthegeneticassociationsof together withthedatafrom ( factors andhighlightitsrolesinneonataldiabetes differentiate GLIS3fromotherpancreatictranscription T2D ( are stronglyassociatedwithbothcommonT1Dand two knownmonogenicdiabetesgeneswhosevariations associated withdiabetes,GLIS3andinsulinaretheonly & Chan 2016 respectively ( 50 and 100 susceptibility loci for common T1D and T2D, Candidate gene studies and GWAS have identified over Conclusions protein response( derived neurotrophicfactor(MANF)duringtheunfolded of acriticalantiapoptoticfactor, mesencephalicastrocyte- susceptibility toapoptosisprobablyduepoorinduction that reducedGLIS3expressionresultsinenhanced developed diabetesuponaging.Theyfurtherreported secretion onNOD glucose intoleranceandincreasedlevelofproinsulin Dooley andcoworkersfoundthat increased susceptibilitytoendoplasmicreticulumstress. NOD autoimmunity againstislets.ComparedtoC57BL/10, of diabetessusceptibilitywithoutspontaneous locus, ageneticmodelusedtodissectthecomponents Idd1 major histocompatibility complex susceptibility genetic background. supported by a recent study in Yang Fig. 2 Table 1 celldevelopment DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Review Glis3 NOD β ), which perturbations may underlie all three forms k geneandneonataldiabetes,commonT1DT2D micearemorepronetoislet cell survival ( cellsurvival ). GLIS3potentlycontrolsinsulingenetranscription Yang &Chan 2016 et al ) aswellinT1DandT2D( globaland k miceharborcongenicreplacementofthepotent . 2009 Todd 2010 ). Among the repertoire of susceptibility loci , 2013 Dooley Yang Kang k in utero geneticbackground.Thesemice Nogueira , β ZeRuth , cell-specificknockoutmodels, et al Bonnefond &Froguel2015 t al et et al ). Theseuniquecharacteristics andmarkedimpairmentin . 2011 . 2016 . 2009 et al t al et β celllines,providethe x Glis3

Glis3 wen ). Anewreportfurther . 2013 © 2017SocietyforEndocrinology . 2013 ). b Table 2 β and , cellfailuredueto +/ +/ Yang GLIS3 − − Yang mice on NOD ) as well aslikely micedeveloped Printed inGreatBritain y ,

yang ). Dooley t al et impairthe et al . 2016 . 2013 , t al et Yang ). k ) .

GLIS3 isrequiredforthemaintenanceofproperadult Moreover, studiesinadultmousemodelsrevealthat Boesgaard TW, GrarupN,JorgensenT, Borch-Johnsen K,Meta-Analysis Beak JY, Kang HS, KimYS&JettenAM2008Functionalanalysisofthe Basile KJ,GuyVC,SchwartzS&GrantSF2014Overlapofgenetic Barrett JC,ClaytonDG,ConcannonP, AkolkarB,CooperJD,ErlichHA, Barker A,SharpSJ,Timpson NJ,Bouatia-NajiN,Warrington NM,Kanoni Awata T, Yamashita H,KuriharaS,Morita-OhkuboT, MiyashitaY, perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest the globalepidemicofT1DandT2D. and potentialtherapeutictargetidentificationtocombat gene willprovidenewinsightsintodiseasepathogenesis different mechanisms.Continuedresearch into likely because they confer their susceptibility effects via with T1D and T2D are unique and do not overlap, people. Ofnote,thevariationsof finding thatthe Ccnd2 induced cell function.GLIS3alsoplaysanessentialroleinobesity- Ackermann AM&GannonM2007Molecularregulationofpancreatic References start-up fundstoYY. to YY)andMetroHealthMedicalCenter, CaseWestern ReserveUniversity partially supportedbyAmericanHeartAssociationgrant(13SDG17090096, Research intheauthors’laboratorythatwasdiscussedthisreview Funding GLIS3 anddiabetes Published byBioscientifica Ltd. 1753-5) Danish people. with reducedglucose-stimulatedbeta cellfunctioninmiddle-aged at DGKB/TMEM195,ADRA2A,GLIS3 andC2CD4Blociareassociated of G,Insulin-RelatedTrait C,HansenT&PedersenO2010Variants gkn009) Glis3(NDH1). zinc fingerandactivationdomainsofGlis3mutant (doi:10.1007/s11892-014-0550-9) autoimmune diabetesinadults. susceptibility totype1diabetes,2andlatent of type1diabetes. association studyandmeta-analysisfindthatover40lociaffectrisk Julier C,MorahanG,NerupJ,NierrasC, (doi:10.2337/db10-1575) meta-analysis ofover6000children. genetic Lociwithglucoselevelsinchildhoodandadolescence:a S, BeilinLJ,BrageDeloukasP, EvansDM, Communications Japanese type1diabetes. 2013 Alow-frequencyGLIS3variantassociatedwithresistanceto Katayama S,KawasakiE,Tanaka S,IkegamiH,MaruyamaT, Molecular Endocrinology beta-cell massdevelopment,maintenance,andexpansion. ( Yang β cell proliferation via the transactivation of et al Nucleic AcidsResearch

Diabetologia 437 . 2013 Nature Genetics GLIS3 521–525.

38 Biochemical andBiophysicalResearch 193–206. locusisalso linked toT2Din ). ThesemayunderlietheGWAS

Downloaded fromBioscientifica.com at09/30/202101:03:31AM 53 1647–1655. (doi:10.1016/j.bbrc.2013.06.102) Current DiabetesReports

36 (doi:10.1677/JME-06-0053) Diabetes 703–707. 1690–1702. et al (doi:10.1007/s00125-010- et al 58

. 2009Genome-wide 60 GLIS3 (doi:10.1038/ng.381) : 2 . 2011Associationof 1805–1812. (doi:10.1093/nar/ associated

14 550. Journal of Journal et al GLIS3 R82 . via freeaccess β

Journal of Molecular Endocrinology Georgia S & Bhushan A 2004 Beta cell replication is the primary Georgia S&BhushanA2004Betacell replicationistheprimary Fujita H,HaraK,ShojimaN,HorikoshiM,IwataHirotaY, Tobe K, Florez JC,JablonskiKA,McAteerJB,FranksPW, MasonCC,MatherK, Dupuis J,LangenbergC,ProkopenkoI,SaxenaR,SoranzoN,Jackson Dou HY, Wang YY, Yang N,HengML,ZhouX,BuHE,XuF, ZhaoTN, Dooley J,Tian L,SchonefeldtS,Delghingaro-AugustoV, Garcia-Perez JE, Donath MY, EhsesJA,MaedlerK,SchumannDM,EllingsgaardH,Eppler Cruchaga C,KauweJS,HarariO,JinSC,CaiY, Karch CM,BenitezBA, Dimitri P, DeFrancoE,HabebAM,GurbuzF, MoussaK,Taha D,Wales Dimitri P, HabebAM,GurbuzF, MillwardA,Wallis S,MoussaK,Akcay Dimitri P, Warner JT, MintonJA,Patch AM,EllardS,HattersleyAT, Barr Cooper LA,GutmanDA,LongQ,JohnsonBA,CholletiSR,Kurc T, Saltz Cho YS,ChenCH,HuC,LongJ,OngRT, SimX,Takeuchi F, Wu Y, Go Cao B,GongC,Wu D,LuC,LiuF, LiuX,ZhangY, GuY, QiZ,Li Bonnefond A&FroguelP2015Rareandcommongeneticeventsin http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0232 Review AU, WheelerE,GlazerNL,Bouatia-NajiN,GloynAL, (doi:10.1007/s11655-015-2290-3) control study. and characteristicsymptomsoftype2diabetes:amatchedcase- Huang H&Wang HW2016Associationbetweengenetic variants 2 diabetes. Genetic predispositionforbetacellfragilityunderliestype1and Clinical Investigation mechanism formaintainingpostnatal betacellmass. (doi:10.1038/jhg.2012.110) diabetes-related traits. important roleinthegeneticbackgroundoftype2diabetesand Seino S&KadowakiT2012Variations withmodesteffectshavean (doi:10.1371/journal.pone.0044424) insulin intheDiabetesPreventionProgram. genetic variantspreviouslyassociatedwithfastingglucoseand Horton E,GoldbergR,DabeleaD,KahnSE, (doi:10.1038/ng.520) impact ontype2diabetesrisk. New geneticlociimplicatedinfastingglucosehomeostasisandtheir Pasciuto E,DiMarinoD,CarrEJ,OskolkovN,Lyssenko V, diabetes.54.suppl_2.S108) diabetes. E &ReineckeM2005Mechanismsofbeta-celldeathintype2 1918–1923. similar 3(GLIS3). recognizable facialphenotypeinassociationwithmutationsGLI- JK, HogueJ,SlavotinekA,ShettyA, jc.2015-1827) Endocrinology andMetabolism spectrum associatedwithGLIS3mutations. T, Taha D,HogueJ,SlavotinekA, of Endocrinology demonstrate anextendedmultisystemphenotype. S, HawkesD,Wales JW 2011NovelGLIS3mutations JK&Gregory 78 fluid taulevelsidentifiesriskvariantsforAlzheimer’s disease. Jeng AT, SkorupaT, CarrellD, pone.0012548) among diffusegliomas. enriched inoligodendrogliomasandpredictsimprovedsurvival JH, BratDJ&MorenoCS2010Theproneuralmolecularsignatureis east Asians. association studiesidentifieseightnewlocifortype2diabetesin MJ, Yamauchi T, 6314368. mellitus patientsinChina. X, 357–368. type 2diabetes:whatshouldbiologistsknow? 256–268. et al . 2016Geneticanalysisandfollow-upof25neonataldiabetes Diabetes (doi:10.1016/j.cmet.2014.12.020) (doi:10.1155/2016/6314368) Nature Genetics (doi:10.1002/ajmg.a.37680) Nature Genetics (doi:10.1016/j.neuron.2013.02.026) Chinese Journal ofIntegrativeMedicine Chinese Journal

164 et al

54 American Journal of Medical Genetics Part A ofMedicalGeneticsPart American Journal

437–443. 114 (Supplement2)S108–S113. . 2012Meta-analysisofgenome-wide Journal ofHumanGenetics Journal PLoS ONE 963–968.

Journal ofDiabetesResearchJournal 44

519–527. 100 67–72. et al (doi:10.1530/EJE-10-0893) Nature Genetics E1362–E1369.

et al 5 . 2013GWAS ofcerebrospinal (doi:10.1172/JCI22098) e12548. et al . 2015Expandingtheclinical x (doi:10.1038/ng.1019)

Cell Metabolism 42

. 2012Effectsof 57 (doi:10.1210/ (doi:10.2337/ 105–116. Printed inGreatBritain y [inpress] European Journal European Journal

776–779. yang Journal of Journal articleID et al

7 e44424. . 2010 et al

170 Neuron

. 2016 . 2016 21

Hu C,ZhangR,Wang C,Wang J,MaX,HouLuYu W, JiangF, Bao Hong KW, ChungM&ChoSB2014Meta-analysisofgenome-wide Herold KC,Vignali DA,CookeA&BluestoneJA2013Type 1diabetes: Hay CW&DochertyK2006Comparativeanalysisofinsulingene Goodarzi MO,GuoX,CuiJ,JonesMR,HarituniansT, XiangAH,Chen Georgia S,HinaultC,KawamoriD,HuJ,MeyerKanjiM,BhushanA Jacquemin P, SM,JensenJ,GodfraindC,GradwohlG, Durviaux Jayachandran A,PrithvirajP, LoPH,Walkiewicz M,AnakaWoods BL, Kiani AK,JohnP, BhattiA,Zia A,ShahidG,AkhtarP, Wang X,Demirci Kang HS,Takeda Y, JeonK&JettenAM2016 Kang HS,ChenLY, Lichti-KaiserK,LiaoG,GerrishBortnerCD,Yao Kang HS,KimYS,ZeRuthG,BeakJY, GerrishK,KilicG,Sosa-PinedaB, Kang HS,BeakJY, KimYS,HerbertR&JettenAM2009 Kim YS,NakanishiG,LewandoskiM &JettenAM2003GLIS3,anovel Khor CC,DoT, JiaH,NakanoM,GeorgeR,Abu-AmeroK,Duvesh GLIS3 anddiabetes Published byBioscientifica Ltd. journal.pone.0015542) metabolism intheChinese. GLIS3, PROX1,SLC30A8andIGF1areassociatedwithglucose Y, (doi:10.1007/s00438-014-0885-6) results. and insulinresistanceinanEastAsianpopulationtheEuropean association studyofhomeostasismodelassessmentbetacellfunction Nature ReviewsImmunology intoeffectiveclinicaloutcomes. translating mechanisticobservations 3201–3213. promoters: implicationsfordiabetesresearch. (doi:10.1007/s00125-013-2880-6) association withinsulinclearance. evaluation ofvalidatedtype2diabetesandglycaemictraitlocifor YD, Taylor KD,BuchananTA, HsuehWA, Diabetes beta-cell hyperplasticresponsetoinsulinresistanceinrodents. & KulkarniRN2010CyclinD2isessentialforthecompensatory targeting determinantsofmelanomacellularinvasion. Tan B,BehrenA,CebonJ&McKeownSJ2016Identifyingand 4445–4454. the proendocrinegenengn3. pancreatic endocrinecelldifferentiationandcontrolsexpressionof 2000 Transcription factorhepatocytenuclear6regulates Guillemot F, MadsenOD,CarmelietP, Dewerchin M,Collen D, development andinbeta,PPductalcells. bipotent andendocrineprogenitorsduringearlypancreatic function in pattern ofGlis3expressionindicatesaregulatory Stem Cells and criticalregulatorofpostnatalstagesmousespermatogenesis. HH, EddyEM&JettenAM2016 Biology development andinsulingeneexpression. Glis3, anovelcriticalplayerintheregulationofpancreaticbeta-cell Jensen J,PierreuxCE,LemaigreFP, 2556–2569. polycystic kidneydisease. ciliaandWwtr1/TAZassociated withprimary andimplicatedin 41186–41202. with repressorandactivationfunctions. member oftheGLISsubfamilyKruppel-like zincfingerproteins 137–142. Pakistani patients. FY &KambohMI2015Associationof32type1diabetesrisklociin glaucoma. angleclosure study identifiesfivenewsusceptibilitylociforprimary Chen LJ,LiZ,NongpiurME, e0157138. 5513–5525. et al . 2010Variants fromGIPR,TCF7L2,DGKB,MADD,CRY2,

29 Molecular GeneticsandGenomics

(doi:10.1016/j.diabres.2015.01.022) 6366–6379. 34 Nature Genetics (doi:10.1371/journal.pone.0157138) 987–996. (doi:10.2337/db06-0788) (doi:10.1128/MCB.20.12.4445-4454.2000) (doi:10.1128/MCB.01620-08) (doi:10.1093/nar/gkg776) 2772–2783. (doi:10.18632/oncotarget.9227) Diabetes Research andClinicalPractice (doi:10.2337/db09-0838) (doi:10.1128/MCB.01259-09)

(doi:10.1002/stem.2449) 48 Molecular andCellularBiology

13 Downloaded fromBioscientifica.com at09/30/202101:03:31AM PLoS ONE 556–562. et al 243–256. Molecular andCellularBiology a . 2016Genome-wideassociation Transcription factorGLIS3:anew Diabetologia et al

(doi:10.1038/ng.3540) . 2009 289 e15542. (doi:10.1038/nri3422) Nucleic AcidsResearch b et al Thespatiotemporal Molecular andCellular 1247–1255. 58 b Diabetes . 2013Systematic PLoS ONE

Transcription factor 56 : 2 (doi:10.1371/ 1282–1290. a Glis3is

Oncotarget

29 108

R83 31

et al

7 via freeaccess

. Journal of Molecular Endocrinology Maestro MA,BojSF, LucoRF, JM, PierreuxCE,CabedoJ,Servitja Oliver-Krasinski JM,KasnerMT, Yang J,CrutchlowMF, RustgiAK, Oliver-Krasinski JM&StoffersDA2008Ontheoriginofbetacell. Nogueira TC,PaulaFM,Villate O,ColliML,MouraRF, CunhaDA, Noble JA,Valdes AM,Cook M,KlitzW, ThomsonG&ErlichHA1996 Morris AP, Voight BF, Teslovich TM,FerreiraT, SegreAV, Steinthorsdottir Moran I,AkermanvandeBuntM,XieR,BenazraNammoT, Arnes Miyazaki S,Yamato E&MiyazakiJ2004Regulatedexpressionofpdx-1 Lynn FC,SmithSB,Wilson ME,Yang KY, NekrepN&GermanMS2007 Lykke-Andersen S&JensenTH2015Nonsense-mediatedmRNAdecay: Lukashova-v ZangenI,KneitzS,MonoranuCM,RutkowskiHinkesB, Liu C,LiH,QiL,LoosRJ,Q,LuGanW&LinX2011Variants in Li H,GanW, LuL,DongX,HanHuC,Yang Z,SunL,BaoW, Li Lee JC,SmithSB,Watada H,LinJ,ScheelD,Wang J,MirmiraRG& MA,SicinskaE,WartschowKushner JA,Ciemerych LM,Teta M,Long Knoll M,LodishHF&SunL2015Longnon-codingRNAsasregulators DOI: 10.1530/JME-16-0232 http://jme.endocrinology-journals.org Review JCI37028) in mice. the transcriptionalnetworkofpancreatic endocrineprogenitorcells Kaestner KH&StoffersDA2009The diabetesgenePdx1regulates Genes andDevelopment journal.pgen.1003532) BH3-only proteinBim. pancreatic betacellapoptosisviaregulationofasplicevariantthe susceptibility genefortype1and2diabetes,modulates Marselli L,Marchetti P, CnopM,JulierC, ofHumanGenetics American Journal mellitus: molecularanalysisof180Caucasian,multiplexfamilies. The roleofHLAclassIIgenesininsulin-dependentdiabetes 44 architecture andpathophysiology oftype2diabetes. scale associationanalysisprovidesinsightsintothegenetic V, StrawbridgeRJ,KhanH,GrallertMahajanA, diabetes. 2 specific, dynamicallyregulated,andabnormallyexpressedintype beta celltranscriptomeanalysisuncoverslncRNAsthataretissue- L, NakicN,Garcia-Hurtado J,Rodriguez-SeguiS, diabetes.53.4.1030) stemcells. embryonic promotes invitrodifferentiationofinsulin-producingcellsfrom 3307–3314. pancreas. cell domainoftheembryonic Tcf2 (MODY5)arelinkedinagenenetworkoperatingprecursor German MS,RousseauGG,LemaigreFP&FerrerJ2003Hnf6and cells. Sox9 coordinatesatranscriptionalnetworkinpancreaticprogenitor Molecular CellBiology thatshapestranscriptomes. an intricatemachinery (doi:10.1007/s00401-006-0190-5) and patientsurvival. expression profilesassociatedwithhistologicalsubtype,proliferation, Vince GH,HuangB&RoggendorfW2007Ependymomagene journal.pone.0021464) fasting glucoseinChineseHans. GLIS3 andCRY2 areassociatedwithtype2diabetesandimpaired 291–298. RASGRP1 astype2diabeteslociinChineseHans. P, neurogenin3. German MS2001Regulationofthepancreaticpro-endocrinegene 25 postnatal pancreaticbeta-cellgrowth. SY, SicinskiP&WhiteMF2005CyclinsD2andD1areessentialfor (doi:10.1038/nrendo.2014.229) of theendocrinesystem. et al 3752–3762. 981–990. PNAS . 2013Agenome-wideassociationstudyidentifiesGRK5and Journal of Clinical Investigation Journal Cell Metabolism (doi:10.2337/db12-0454)

104 (doi:10.1093/hmg/ddg355) (doi:10.1038/ng.2383) Diabetes (doi:10.1128/MCB.25.9.3752-3762.2005) 10500–10505.

Acta Neuropathologica 16

Diabetes 50 22 PLoS Genetics

665–677. 16 928–936. Nature ReviewsEndocrinology 1998–2021. 435–448.

(doi:10.1073/pnas.0704054104) 53 PLoS ONE 1030–1037. (doi:10.1038/nrm4063)

59 (doi:10.2337/diabetes.50.5.928)

9 (doi:10.1016/j.cmet.2012.08.010) x 1134–1148. Molecular andCellularBiology e1003532.

(doi:10.1101/gad.1670808) 119

113 1888–1898. 6 and e21464. . 2013GLIS3,a (doi:10.2337/ 325–337. et al Printed inGreatBritain y (doi:10.1371/ Diabetes et al

. 2012 Human . 2012Human Nature Reviews yang

Nature Genetics 11 (doi:10.1371/ . 2012Large- (doi:10.1172/ 151–160.

Porcu E,MediciM,PistisG,Volpato CB,Wilson SG,CappolaAR,Bos Yang Y, ChangBH,SamsonSL,LiMV&ChanL2009TheKruppel-like Yang Y&ChanL2016MonogenicDiabetes:Whatitteachesus onthe Winkler C,KrumsiekJ,BuettnerF, Angermuller C,GiannopoulouEZ, Watanabe N,HiramatsuK,MiyamotoR,Yasuda K,SuzukiN,Oshima Todd JA2010Etiologyof type1diabetes. Taha D,BarbarM,KanaanH&Williamson BalfeJ2003Neonatal Steinthorsdottir V, ThorleifssonG,SulemP, HelgasonH,GrarupN, Steck AK,DongF, Wong R,FoutsA,LiuE,RomanosJ,Wijmenga C, Shih HP, Wang A&SanderM2013Pancreasorganogenesis:from Santin I&EizirikDL2013Candidategenesfortype1diabetesmodulate Sakai K,ImamuraM,Tanaka Y, IwataM, HiroseH,KakuK,Maegawa Rual JF, Venkatesan K,HaoT, Hirozane-KishikawaT, DricotA,LiN, Rees SD,HydrieMZ,O’HareJP, KumarS,SheraAS,BasitA,BarnettAH Rami F, BaradaranA,KahnamooiMM&SalehiM2016Alterationof Senee V, ChelalaC,DuchateletS,FengD,BlancH, CossecJC,Charon GLIS3 anddiabetes Published byBioscientifica Ltd. 190–222. common formsoftype1and 2 diabetes. Diabetologia diabetes susceptibilitygenesimprovespredictionoftype1diabetes. Theis FJ,ZieglerAG&BonifacioE2014Featurerankingoftype1 Letters model ofneonataldiabetesmellitusinGlis3-deficientmice. Kiyonari H,ShibaD,NishioS,MochizukiT, (doi:10.1016/j.immuni.2010.04.001) 269–273. recessive syndrome? polycystic kidneys,andcongenitalglaucoma:anewautosomal diabetes mellitus,congenitalhypothyroidism,hepaticfibrosis, pancreatic isletinflammationandbeta-cellapoptosis. (doi:10.1371/journal.pone.0076317) type 2diabetesinaJapanesepopulation. association of9EastAsianGWAS-derived lociwithsusceptibilityto Watada H,Tobe K,KashiwagiA, nature04209) interaction network. Towards aproteome-scalemapofthehumanprotein-protein Berriz GF, GibbonsFD,DrezeM,Ayivi-Guedehoussou N, journal.pone.0024710) predispose totype2diabetes. and type2diabetesinSouthAsians:ADCY5GLIS3variantsmay & KellyMA2011Effectsof16geneticvariantsonfastingglucose differences intheregulationofthyroidfunction. of thyroid-relatedtraitsrevealsnovellociandgender-specific SD, DeelenJ,denHeijerM,FreathyRM, zinc fingerproteinGlis3directlyand indirectlyactivatesinsulin diabetes. sequence variantsassociatedwithelevatedorreducedriskoftype2 Gudjonsson SA, Sigurdsson A,HelgadottirHT, JohannsdottirH,MagnussonOT, Pediatric Diabetes by testingnon-HLAgeneticvariantsinadditiontoHLAmarkers. Norris JM&RewersMJ2014Improvingpredictionoftype1diabetes cellbio-101512-122405) Developmental Biology lineage determinationtomorphogenesis. 682–687. mellitus andcongenitalhypothyroidism. GLIS3 areresponsibleforararesyndromewithneonataldiabetes C, NicolinoM,BoileauP, CavenerDR, dom.12162) Obesity andMetabolism Advanced BiomedicalResearch GLIS3 geneexpressionpatterninpatientswithbreastcancer. e1003266.

583 Nature Genetics (doi:10.1210/er.2015-1116) (doi:10.1002/ajmg.a.20267) (doi:10.1038/ng1802) 2108–2113. (doi:10.1371/journal.pgen.1003266)

57 2521–2529. et al

15 355–362. . 2014Identificationoflow-frequencyandrare American Journal of Medical Genetics Part A ofMedicalGeneticsPart American Journal

Nature 29

15 (doi:10.1016/j.febslet.2009.05.039)

81–105. 46 (Supplement3)71–81.

294–298. Downloaded fromBioscientifica.com at09/30/202101:03:31AM (doi:10.1007/s00125-014-3362-1) 437

5 PLoS ONE 44. (doi:10.1111/pedi.12092) 1173–1178. et al (doi:10.1146/annurev- (doi:10.4103/2277-9175.178803) . 2013Replicationstudyforthe (doi:10.1038/ng.2882) Immunity et al

6 et al Nature Genetics Annual ReviewofCelland PLoS ONE e24710. . 2006Mutationsin 58 et al (doi:10.1038/ . 2013Ameta-analysis Endocrine Reviews

: 2 32 . 2009Amurine PLoS Genetics (doi:10.1111/ 457–467. (doi:10.1371/

8 e76317. Diabetes

38 et al

FEBS . 2005 R84

9 122A

37 via freeaccess

Journal of Molecular Endocrinology Yang Y, BushSP, Wen X,CaoW&ChanL2016Differentialgenedosage Yang Y, ChangBH&ChanL2013Sustainedexpressionofthe Yang Y, ChangBH,Yechoor V, ChenW, LiL,Tsai MJ&ChanL2011 http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0232 Review en.2016-1541) differentiation andfunction. effects ofdiabetes-associatedgeneGLIS3inpancreaticbetacell emmm.201201398) in adults. transcription factorGLIS3isrequiredfornormalbetacellfunction 54 3 forproperfetalpancreaticisletdifferentiationinmice. The Kruppel-likezincfingerproteinGLIS3transactivatesneurogenin (doi:10.1093/nar/gkp122) gene transcription. 2595–2605. EMBO MolecularMedicine . (doi:10.1007/s00125-011-2255-9) Nucleic AcidsResearch Endocrinology

5 92–104. x

wen

yang (doi:10.1210/ Diabetologia

Yusenko MV&KovacsG2009IdentifyingCD82(KAI1)asamarkerfor ZeRuth GT, Williams JG,ColeYC&JettenAM2015HECTE3ubiquitin ZeRuth GT, Takeda Y&JettenAM2013TheKruppel-likeproteinGli- ZeRuth GT, Yang XP&JettenAM2011Modulationofthetransactivation Accepted Preprintpublishedonline29November2016 Accepted 25November2016 Received infinalform16November2016 GLIS3 anddiabetes Published byBioscientifica Ltd. journal.pone.0131303) (Glis3) transcriptionalactivity. ligase itchfunctionsasanovelnegativeregulatorofgli-similar3 Molecular Endocrinology similar 3(Glis3)functionsasakeyregulatorofinsulintranscription. 22077–22089. (Glis3) bySuppressorofFused. 3 function andstabilityofKruppel-likezincfingerproteinGli-similar 687–695. human chromophoberenalcellcarcinoma. (doi:10.1111/j.1365-2559.2009.03449.x) (doi:10.1074/jbc.M111.224964)

27 1692–1705. Downloaded fromBioscientifica.com at09/30/202101:03:31AM Journal ofBiologicalChemistry Journal PLoS ONE (doi:10.1210/me.2013-1117)

10 Histopathology e0131303. 58 : 2 (doi:10.1371/

286

R85 via freeaccess