Affinage

GLIS3

Zinc finger protein GLIS3 · UniProt Q8NEA6

Length
775 aa
Mass
83.6 kDa
Annotated
2026-04-28
84 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLIS3 is a Krüppel-like zinc finger transcription factor that functions as a master regulator of pancreatic beta cell development and function, thyroid hormone biosynthesis, renal metabolic homeostasis, and intestinal fibroblast inflammatory programming. It binds the consensus sequence (G/C)TGGGGGGT(A/C) through five C2H2-type zinc fingers, with the C-terminus providing transactivation activity; at the insulin promoter, GLIS3 acts as a scaffold recruiting CBP/p300, Pdx1, MafA, and NeuroD1, and it drives endocrine progenitor specification by directly transactivating Neurogenin 3 in cooperation with Hnf6 and FoxA2 (PMID:14500813, PMID:19264802, PMID:23927931, PMID:21786021). GLIS3 protein stability and transcriptional output are tuned by ubiquitination (via Itch and Cullin3-based E3 ligases, antagonized by SUFU) and SUMOylation (via PIASy/Ubc9), and in beta cells GLIS3 loss promotes apoptosis through alternative splicing of pro-apoptotic Bim via SRp55 (PMID:21543335, PMID:26147758, PMID:30094379, PMID:23737756). Loss-of-function mutations in GLIS3 cause neonatal diabetes and congenital hypothyroidism in humans; in thyroid, GLIS3 operates downstream of TSH/TSHR to co-activate iodide transporter genes with PAX8, NKX2.1, and FOXE1, and in kidney it directly controls mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation genes while repressing PKM2-driven aerobic glycolysis, with its loss causing cystogenesis (PMID:16715098, PMID:29083325, PMID:36793061, PMID:39505148, PMID:41826646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    Identification of GLIS3 as a dual-function Krüppel-like zinc finger transcription factor that binds GLI-response elements established the molecular framework for all subsequent functional studies.

    Evidence Reporter assays, deletion mutant analysis, DNA-binding assays, and in situ hybridization in the original characterization paper

    PMID:14500813

    Open questions at the time
    • No endogenous target genes identified
    • No in vivo function demonstrated
    • No post-translational regulation characterized
  2. 2006 High

    Discovery that loss-of-function GLIS3 mutations cause neonatal diabetes and congenital hypothyroidism in humans established its essential non-redundant role in beta cell and thyroid development, directing subsequent mechanistic work toward these tissues.

    Evidence Identification of frameshift and large deletions in multiple consanguineous families with neonatal diabetes and hypothyroidism

    PMID:16715098

    Open questions at the time
    • Molecular targets in beta cells and thyroid unknown
    • Developmental stage of GLIS3 requirement undefined
  3. 2008 High

    Mapping of the DNA-binding determinants (all five zinc fingers required, consensus (G/C)TGGGGGGT(A/C)) and localization of the transactivation domain to the C-terminus explained how the human NDH1 frameshift mutation causes disease — by truncating transactivation while preserving nuclear localization.

    Evidence EMSA with systematic zinc finger mutants, reporter assays with deletion constructs, analysis of NDH1 mutation

    PMID:18263616

    Open questions at the time
    • No genome-wide binding data
    • No crystal structure of zinc finger–DNA complex
  4. 2009 High

    Demonstration that GLIS3 directly binds the insulin promoter and physically interacts with Pdx1, MafA, and NeuroD1 provided the first mechanistic explanation for how GLIS3 loss causes neonatal diabetes, while concurrent work showed GLIS3 localizes to primary cilia and interacts with Wwtr1/TAZ, linking it to cilia-dependent signaling and polycystic kidney disease.

    Evidence ChIP, EMSA, co-IP, reporter assays (insulin promoter); confocal localization to cilia; Glis3 KO mouse developing PKD

    PMID:19264802 PMID:19273592 PMID:19481545

    Open questions at the time
    • Whether GLIS3 acts as a scaffold versus simple activator at the insulin promoter was not resolved
    • Cilia-to-nucleus signaling mechanism unknown
    • Wwtr1/TAZ contribution in vivo untested
  5. 2011 High

    Placing GLIS3 upstream of Neurogenin 3 in the endocrine differentiation hierarchy — via direct promoter binding and synergy with Hnf6 and FoxA2 — and identifying SUFU as a stabilizer that antagonizes Cullin3-mediated GLIS3 degradation revealed both a developmental circuit and a proteostatic control mechanism.

    Evidence ChIP and reporter assays on Ngn3 promoter with epistasis in Glis3−/− mice; co-IP, ubiquitination assays, and mutagenesis for SUFU/Cullin3 axis

    PMID:21543335 PMID:21786021

    Open questions at the time
    • Identity of the Cullin3 adaptor for GLIS3 unknown
    • Whether SUFU regulation occurs in primary cilia unresolved
    • In vivo significance of SUFU–GLIS3 interaction in beta cells untested
  6. 2012 High

    Conditional deletion in adult beta cells proved that GLIS3 is continuously required — not just developmentally — for insulin expression and beta cell mass maintenance, including proliferative adaptation to metabolic stress via Cyclin D2 regulation.

    Evidence Tamoxifen-inducible Glis3 conditional KO in adult mice, glucose tolerance testing, Ccnd2 expression analysis

    PMID:22820919 PMID:23197416

    Open questions at the time
    • Whether GLIS3 directly binds the Ccnd2 promoter not shown by ChIP
    • Mechanism linking GLIS3 loss to proliferative failure beyond Ccnd2 unclear
  7. 2013 High

    Two mechanistic advances resolved how GLIS3 controls beta cell fate: it functions as an obligate scaffold at the insulin promoter (recruiting CBP/p300 for stable Pdx1/MafA association), and its loss triggers beta cell apoptosis through SRp55-mediated alternative splicing of pro-apoptotic Bim — an unexpected splicing-regulatory function.

    Evidence GlisBS mutagenesis with ChIP showing loss of Pdx1/MafA binding; Bim splice variant analysis with SRp55 mechanism and Bim-KD rescue in INS-1E, primary rat beta cells, and human islets

    PMID:23737756 PMID:23927931

    Open questions at the time
    • How GLIS3 regulates SRp55 expression or activity unknown
    • Whether the scaffold function is unique to the insulin promoter or general
  8. 2015 High

    Identification of Itch as a second E3 ubiquitin ligase for GLIS3 (acting via N-terminal PPxY motifs) complemented the earlier Cullin3 finding, revealing dual proteolytic control of GLIS3 protein levels that tunes insulin gene output.

    Evidence Mass spectrometry, yeast two-hybrid, co-IP, ubiquitination assays, proteasome inhibitor experiments, and mutagenesis

    PMID:26147758

    Open questions at the time
    • Relative contributions of Itch vs. Cullin3 in beta cells in vivo unknown
    • No deubiquitinase identified
  9. 2017 High

    ChIP-Seq in thyroid placed GLIS3 downstream of TSH/TSHR signaling as a direct activator of iodide transporter genes (Nis, Pds) and revealed that GLIS3 is required for mTORC1-dependent thyroid proliferation, providing a molecular explanation for congenital hypothyroidism.

    Evidence GLIS3 ChIP-Seq in thyroid, mTORC1/RPS6 signaling analysis, and Glis3-deficient mouse thyroid phenotyping

    PMID:29083325

    Open questions at the time
    • How TSH signaling induces GLIS3 expression or activity unknown
    • mTORC1 activation mechanism downstream of GLIS3 not defined
  10. 2018 High

    SUMOylation of GLIS3 at conserved N-terminal lysines (by PIASy/Ubc9) was shown to inhibit insulin transcription under chronic high-glucose conditions, providing a post-translational mechanism linking glucotoxicity to beta cell dysfunction; concurrently, GLIS3 loss in hESC-derived beta cells was shown to activate TGFβ-mediated cell death, identifying a druggable pathway.

    Evidence SUMOylation assays with mutagenesis under variable glucose; GLIS3−/− hESC differentiation with chemical screen and xenograft rescue

    PMID:29992946 PMID:30094379

    Open questions at the time
    • SUMO site occupancy in native beta cells not measured
    • Identity of TGFβ ligands and receptors mediating GLIS3−/− beta cell death unresolved
    • Drug target specificity not fully defined
  11. 2019 High

    Genome-wide ChIP-Seq in beta cells expanded the direct GLIS3 target repertoire to include Slc2a2/Glut2 and MafA, showing that GLIS3 loss produces a PDX1+/INS−/MAFA−/GLUT2− dedifferentiated beta cell state rather than simply causing cell death, reshaping the understanding of GLIS3-associated diabetes pathogenesis.

    Evidence GLIS3 ChIP-Seq and RNA-Seq in islets from pancreas-specific conditional KO mice

    PMID:31340201

    Open questions at the time
    • Whether dedifferentiated cells can be re-differentiated by GLIS3 restoration untested
    • Distinction between dedifferentiation and alternative cell fate not resolved
  12. 2023 High

    Integration of GLIS3, PAX8, NKX2.1, and FOXE1 cistromes in thyroid revealed extensive co-occupancy at thyroid gene regulatory regions; GLIS3 loss did not alter co-factor binding or histone marks, suggesting GLIS3 activates transcription by enhancing enhancer–promoter communication or Pol II recruitment rather than restructuring chromatin.

    Evidence Multi-TF ChIP-Seq in mouse thyroid and PCCl3 cells, histone mark ChIP-qPCR in Glis3 KO

    PMID:36793061

    Open questions at the time
    • Enhancer–promoter looping assays (e.g., HiChIP) not performed
    • Whether this non-chromatin-remodeling mechanism applies in beta cells unknown
  13. 2024 High

    Discovery that GLIS3 directly controls mitochondrial biogenesis, OXPHOS, and fatty acid oxidation genes in kidney — co-binding with HNF1B and NRF1 — and that GLIS3 loss causes metabolic reprogramming toward aerobic glycolysis (via PKM2 de-repression) that drives cystogenesis, established a metabolic mechanism for GLIS3-associated polycystic kidney disease and a pharmacological target (PKM2 inhibition).

    Evidence ChIP-Seq, untargeted metabolomics, Seahorse respirometry, and PKM2 inhibitor rescue in tissue-specific KO mice and spheroid cultures

    PMID:39505148 PMID:41826646

    Open questions at the time
    • Whether the metabolic switch is reversible in vivo with GLIS3 restoration not tested
    • Contribution of other glycolytic enzymes beyond PKM2 unclear
    • HNF1B and NRF1 functional interdependence with GLIS3 not dissected by combinatorial KO
  14. 2026 High

    Genome-wide CRISPR screens identified GLIS3 as a key transcriptional regulator of an inflammatory-fibrotic gene network in intestinal fibroblasts, extending its role beyond endocrine and renal tissues; fibroblast-specific Glis3 deletion alleviated chronic colitis, establishing GLIS3 as a driver of inflammation-associated fibrosis.

    Evidence CRISPR KO/activation screens, fibroblast-specific conditional KO mouse, single-cell and spatial transcriptomics in colitis model

    PMID:41501466

    Open questions at the time
    • Direct GLIS3 target genes in fibroblasts not defined by ChIP
    • Upstream signals (beyond FCN1+IL1B+ macrophages) inducing GLIS3 in fibroblasts unknown
    • Relevance to human inflammatory bowel disease not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the structural basis of GLIS3–DNA interaction and how its five zinc fingers cooperate; the cilia-to-nucleus signaling pathway that regulates GLIS3 processing or activation; and whether the metabolic, splicing-regulatory, and chromatin-remodeling functions of GLIS3 operate through common or distinct co-factor complexes across tissues.
  • No crystal or cryo-EM structure of GLIS3 zinc finger domain bound to DNA
  • Ciliary signaling mechanism for GLIS3 activation entirely undefined
  • Tissue-specific co-factor repertoire not systematically compared

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 13 GO:0003677 DNA binding 9
Localization
GO:0005634 nucleus 5 GO:0005929 cilium 1
Pathway
R-HSA-74160 Gene expression (Transcription) 13 R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
FOXA2HNF6ITCHMAFANEUROD1PDX1SUFUWWTR1

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 GLIS3 is an 83.8 kDa nuclear protein containing five C2H2-type Krüppel-like zinc finger motifs that can function as both a repressor and activator of transcription; it binds the GLI-RE consensus sequence and enhances GLI-RE-dependent transcription; deletion mutant analysis showed the N- and C-termini are required for optimal transcriptional activity. Reporter assays, deletion mutant analysis, DNA-binding assays, whole-mount in situ hybridization Nucleic acids research High 14500813
2006 Loss-of-function mutations in GLIS3 (frameshift and large deletions) cause neonatal diabetes and congenital hypothyroidism; GLIS3 is expressed preferentially in pancreatic beta cells and thyroid from early developmental stages, establishing its role in beta cell and thyroid development. Human genetic mutation identification, gene expression analysis (tissue-specific transcripts) Nature genetics High 16715098
2008 The fourth zinc finger tetrahedral configuration is essential for nuclear localization of GLIS3 (not the putative bipartite NLS); all five zinc finger motifs are critical for efficient DNA binding; the consensus high-affinity Glis3 DNA-binding site is (G/C)TGGGGGGT(A/C); the C-terminus contains the transactivation domain; the NDH1 frameshift mutation truncates the C-terminus, abolishing transactivating activity without affecting nuclear localization. Deletion mutant analysis, EMSA (electrophoretic mobility shift assay), reporter transcription assays, mutagenesis Nucleic acids research High 18263616
2009 GLIS3 localizes to the primary cilium as well as the nucleus; GLIS3 interacts with the transcriptional coactivator Wwtr1/TAZ via a P/LPXY motif in the GLIS3 C-terminus; Wwtr1 enhances GLIS3-mediated transcriptional activation; mutations in the P/LPXY motif abrogate both Wwtr1 interaction and transcriptional activity; Glis3-deficient mice develop polycystic kidney disease. Co-immunoprecipitation, subcellular localization (confocal imaging), reporter assays, mutagenesis, mouse knockout model Molecular and cellular biology High 19273592
2009 Glis3 directly binds the insulin 2 (Ins2) promoter at a Glis3 response element (5'-GTCCCCTGCTGTGAA-3', positions -255 to -241) via its zinc finger region; Glis3 physically and functionally interacts with Pdx1, MafA, and NeuroD1 to modulate Ins2 promoter activity; Glis3 also upregulates MafA and downregulates Nkx6-1. Chromatin immunoprecipitation (ChIP), EMSA, reporter/deletion assays, co-immunoprecipitation, siRNA knockdown Nucleic acids research High 19264802
2009 Glis3-deficient mice exhibit neonatal diabetes due to impaired islet development and decreased insulin mRNA, establishing GLIS3 as essential for insulin-producing cell formation in vivo. Gene-targeted knockout mouse, blood glucose measurement, insulin mRNA quantification, histology FEBS letters High 19481545
2011 GLIS3 directly binds specific GLIS3-response elements in the Neurogenin 3 (Neurog3/Ngn3) promoter and activates Neurog3 transcription; GLIS3 acts synergistically with Hnf6 and FoxA2 to activate Ngn3, placing GLIS3 upstream of Neurog3 in the endocrine pancreas differentiation hierarchy. In vivo genetic analysis (Glis3-/- mouse), ChIP, promoter reporter assays, epistasis, in vitro reconstitution Diabetologia High 21786021
2011 SUFU interacts with GLIS3 through a VYGHF motif in the conserved N-terminal region of GLIS3; SUFU inhibits GLIS3-mediated insulin promoter activation in a binding-dependent manner; SUFU promotes nuclear accumulation of itself when GLIS3 is present; SUFU stabilizes GLIS3 by antagonizing a Cullin 3-based E3 ubiquitin ligase that ubiquitinates and degrades GLIS3. Co-immunoprecipitation, reporter assays, mutagenesis, ubiquitination assays, subcellular localization The Journal of biological chemistry High 21543335
2007 GLIS3 promotes osteoblast differentiation in multipotent C3H10T1/2 cells, acts synergistically with BMP2 and Shh, and induces FGF18 expression via a Glis3 binding site in the FGF18 promoter flanking region; the C-terminal activation function is required for this effect. Microarray, reporter assays, EMSA, alkaline phosphatase activity, siRNA/overexpression Journal of bone and mineral research Medium 17488195
2012 Glis3 directly interacts with Hnf6 in vitro and in vivo; the Glis3 N-terminus and the Hnf6 homeodomain are required for this interaction; both proteins cooperatively activate Ngn3 transcription through the distal Ngn3 promoter region. Co-immunoprecipitation, in vitro binding assay, ChIP, reporter assays, deletion/mutagenesis Molecules and cells High 22820919
2012 Sustained GLIS3 expression in adult beta cells is required for insulin expression and beta cell mass maintenance; GLIS3 controls beta cell proliferation in response to high-fat diet by regulating Ccnd2 (Cyclin D2) transcription. Conditional knockout mouse (Glis3fl/fl/Pdx1CreERT+), tamoxifen induction, glucose tolerance testing, gene expression analysis EMBO molecular medicine High 23197416
2013 GLIS3 knockdown increases beta cell apoptosis via the intrinsic (mitochondrial) pathway (cytochrome c release, Bax translocation, caspase 9/3 activation); GLIS3 loss promotes alternative splicing of the pro-apoptotic BH3-only protein Bim, favouring the pro-death variant BimS via inhibition of the splicing factor SRp55; KD of Bim abrogates the pro-apoptotic effect of GLIS3 loss. siRNA knockdown in INS-1E cells, primary rat beta cells and human islets; cytochrome c fractionation; Bax translocation; caspase activity assays; RT-PCR for splice variants PLoS genetics High 23737756
2013 GLIS3 binding to GlisBS in the insulin promoter is required as a scaffold for the stable association of Pdx1, NeuroD1, and MafA with the insulin promoter; GLIS3 recruits CBP/p300 to form a larger transcriptional regulatory complex; GlisBS mutation prevents stable Pdx1 and MafA binding and reduces insulin promoter activation by all three factors. ChIP, reporter assays, siRNA knockdown, GlisBS mutagenesis, co-immunoprecipitation Molecular endocrinology High 23927931
2015 The HECT E3 ubiquitin ligase Itch interacts with GLIS3 through WW domain–PPxY motif interaction in the GLIS3 N-terminus, polyubiquitinates GLIS3, and enhances its proteasomal degradation, thereby inhibiting GLIS3-mediated transactivation and endogenous Ins2 expression; Itch-mediated degradation requires both the PPxY motif and GLIS3 zinc finger domains. Mass spectrometry, yeast 2-hybrid, co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, reporter assays, mutagenesis PloS one High 26147758
2016 Glis3 is expressed in bipotent progenitors in the trunk domain (co-localizing with Sox9, Hnf6, Pdx1), in Ngn3+ endocrine progenitors, and in mature beta, PP, and ductal cells (but not in multipotent tip progenitors); Glis3-deficiency reduces and exogenous Glis3 induces Ppy (pancreatic polypeptide) expression. Glis3-EGFP knockin mouse, immunohistochemistry, live imaging, co-localization analysis PloS one High 27270601
2016 GLIS3 is expressed in gonocytes, spermatogonial stem cells (SSCs), and spermatogonial progenitors; loss of GLIS3 impairs gonocyte-to-SSC transition and inhibits cytoplasmic-to-nuclear translocation of FOXO1 (a marker of gonocyte-to-SSC transition required for SSC self-renewal). GLIS3 knockout mice, gene expression profiling, immunohistochemistry, FOXO1 localization assay Stem cells High 27350140
2017 GLIS3 acts downstream of TSH/TSHR signaling and is indispensable for TSH/TSHR-mediated thyroid follicular cell proliferation and thyroid hormone biosynthesis; ChIP-Seq showed GLIS3 directly binds and activates promoters of Nis (Slc5a5) and Pds (Slc26a4) iodide transporters; GLIS3 deficiency inhibits mTORC1/RPS6 pathway activation downstream of TSH, suppressing cell division. GLIS3-deficient mouse model, ChIP-Seq, promoter analysis, mTORC1/RPS6 signaling assays, proliferation assays The Journal of clinical investigation High 29083325
2018 SUMO modification of GLIS3 at two conserved lysine residues in the N-terminus, mediated by PIASy and Ubc9, dramatically inhibits GLIS3-mediated insulin transcription; SUMOylation of GLIS3 is increased under chronically elevated glucose conditions and correlates with decreased insulin transcription. SUMOylation assays, reporter assays, mutagenesis of lysine residues, glucose treatment experiments Heliyon Medium 30094379
2018 GLIS3 directly activates WNT gene transcription (including WNT3A) in human embryonic stem cells, driving their differentiation toward posterior neural progenitor cells; inhibition of WNT signaling abrogates GLIS3-induced posterior specification. RNA-Seq, ChIP-Seq, functional reporter assays, WNT inhibition rescue experiments, hESC differentiation Stem cells High 30376208
2018 Loss of GLIS3 in hESC-derived pancreatic progenitors causes beta-cell death by activating the TGFβ pathway; a drug screen identified a compound that rescues GLIS3-/- associated beta-cell death in vitro and in vivo. GLIS3-/- hESC directed differentiation, high-content chemical screen, TGFβ pathway analysis, in vivo xenograft Nature communications High 29992946
2019 GLIS3 binds pancreatic beta cell regulatory regions that coincide with binding sites for other islet-enriched transcription factors; ChIP-Seq combined with RNA-Seq revealed direct regulation of Slc2a2 (Glut2) and Mafa by GLIS3 in addition to Ins2 and Ngn3; loss of GLIS3 in beta cells produces PDX1+/INS-/MAFA-/GLUT2- cells without increased cell death. Pancreas-specific Glis3 conditional KO, GLIS3 ChIP-Seq, islet RNA-Seq, immunohistochemistry The Journal of endocrinology High 31340201
2019 GLIS3 is required for self-renewal of adult murine pancreatic colony-forming units (PCFUs); GLIS3 maintains WNT receptor and signaling molecule expression (a GLIS3-CD133-WNT axis); CD133 (but not GLIS3 or WNT) is required for PI3K/AKT-mediated PCFU survival. shRNA knockdown in sorted CD133highCD71low ductal cells, ex vivo colony/organoid assays, gene expression analysis The Journal of biological chemistry Medium 31533988
2018 Loss of Glis3 in fetal male germ cells causes widespread reduction in retrotransposon silencing factors and aberrant retrotransposon expression; precocious Glis3 expression in vivo results in premature expression of piRNA pathway members, indicating GLIS3 is necessary for activation of retrotransposon silencing programs. Glis3 KO mouse, gene expression profiling, in vivo transgenic induction of Glis3 Scientific reports Medium 29941866
2023 GLIS3 co-regulates transcription of thyroid hormone biosynthetic genes (including Slc5a5/Nis, Slc26a4, Cdh16, Adm2) by binding within the same regulatory regions as PAX8, NKX2.1, and FOXE1; loss of GLIS3 does not significantly alter PAX8 or NKX2.1 binding or H3K4me3/H3K27me3 epigenetic marks, suggesting GLIS3 activates transcription by enhancing interactions with enhancers and/or RNA Pol II complexes rather than restructuring chromatin. PAX8/NKX2.1/FOXE1 ChIP-Seq in mouse thyroid and PCCl3 cells, comparison to GLIS3 cistrome, ChIP-QPCR, histone mark analysis in Glis3KO Cell & bioscience High 36793061
2024 GLIS3 directly regulates genes critical for mitochondrial biogenesis, OXPHOS, fatty acid oxidation, and TCA cycle in kidney (including Tfam, Ppargc1a/b, Hadha, Sdha); GLIS3 ChIP-Seq showed binding near these genes; GLIS3 binding loci frequently co-localize with HNF1B and NRF1; loss of GLIS3 causes metabolic reprogramming toward aerobic glycolysis and glutamine anaplerosis in kidney. Transcriptomics, ChIP-Seq (cistromics), untargeted metabolomics, Seahorse analysis, tissue-specific KO mice Molecular metabolism High 39505148
2024 GLIS3 directly represses Pkm (pyruvate kinase M) expression in kidney; loss of GLIS3 elevates PKM2 dimer-promoting phosphorylations (Y105, S37) and increases aerobic glycolysis; pharmacological inhibition of PKM2 in GLIS3-deficient cultures and kidneys reduces cyst growth, linking GLIS3-mediated glycolytic repression to cystogenesis. Transcriptomics, ChIP-Seq, siRNA knockdown, phosphorylation analysis, PKM2 inhibitor treatment, spheroid/cyst assays Experimental & molecular medicine High 41826646
2020 In zebrafish, glis3 is required for early thyroid primordium specification; glis3 morphants show reduced nkx2.4 and pax2a expression at the thyroid primordium; glis3 functions as an effector of the Sonic Hedgehog (SHH) pathway in thyroid development; pharmacological SHH inhibition reproduces thyroid defects seen in glis3 morphants. Morpholino knockdown in zebrafish, in situ hybridization, immunohistochemistry, pharmacological SHH inhibition Thyroid Medium 31797737
2020 The PAX8-GLIS3 fusion oncogene (exons 1-2 of PAX8 fused to exons 3-11 of GLIS3) increases proliferation, clonogenic potential, and migration of thyroid and HEK-293 cells; these oncogenic effects are mediated through activation of the Sonic Hedgehog (SHH) pathway; SMO inhibitor cyclopamine partially reverses these effects. Forced expression in cell lines, proliferation/migration assays, xenograft models, SHH pathway inhibition International journal of cancer High 32383186
2023 CircGlis3, derived from exon 4 of Glis3, promotes beta-cell dysfunction by: (1) binding hnRNPF and blocking its nuclear translocation, thereby reducing Sirt1 levels; (2) encoding a 348aa protein that interacts with GLIS3 and inhibits its transcriptional activity; CELF1 facilitates biogenesis of circGlis3. Transgenic mouse model, RNA pulldown, protein interaction assays, nuclear fractionation, CRISPR overexpression iScience Medium 38226164
2024 Glis3 acts as a pioneer-like factor at the insulin promoter, permissively remodeling chromatin to allow access by Pdx1 and MafA; Glis3 positively regulates MafA transcription through its pancreas-specific promoter; MafA reciprocally regulates Glis3 expression; Glis3 is downregulated by oxidative stress in glucotoxic conditions. CRISPR/Cas9 knockdown, chromatin accessibility assays, reporter assays, gene expression analysis in INS1 cells under high glucose Islets Medium 38652652
2026 GLIS3 is a key transcriptional regulator of an inflammation-fibrosis cell circuit in intestinal fibroblasts; fibroblast-specific deletion of Glis3 in mice alleviates chronic colitis; GLIS3 governs expression of inflammatory and fibrotic genes in inflammation-associated fibroblasts induced by FCN1+IL1B+ macrophages, which in turn produce profibrotic IL-11. Genome-wide CRISPR knockout and activation screens, fibroblast-specific conditional KO mouse, single-cell and spatial transcriptomics, colitis model Nature High 41501466
2025 Alternative splicing of mouse Glis3 produces a shorter isoform lacking exon 3 (659 aa vs. 935 aa); the shorter isoform is expressed at higher levels in all mouse tissues, is more stable, and exhibits greater transactivation potential; mass spectrometry identified phosphorylation sites and co-activator/co-repressor complex members (including known members) as GLIS3 interactors. RT-PCR, isoform-specific expression analysis, stability assays, reporter assays, mass spectrometry Cells Medium 41369402

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nature genetics 287 16715098
2013 GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS genetics 144 23737756
2003 GLIS3, a novel member of the GLIS subfamily of Krüppel-like zinc finger proteins with repressor and activation functions. Nucleic acids research 107 14500813
2009 Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease. Molecular and cellular biology 88 19273592
2010 Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people. Diabetologia 82 20419449
2010 Novel GLIS3 mutations demonstrate an extended multisystem phenotype. European journal of endocrinology 73 21139041
2009 The Krüppel-like zinc finger protein Glis3 directly and indirectly activates insulin gene transcription. Nucleic acids research 73 19264802
2009 A murine model of neonatal diabetes mellitus in Glis3-deficient mice. FEBS letters 72 19481545
2017 GLIS3 is indispensable for TSH/TSHR-dependent thyroid hormone biosynthesis and follicular cell proliferation. The Journal of clinical investigation 62 29083325
2008 Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1). Nucleic acids research 61 18263616
2015 Expanding the Clinical Spectrum Associated With GLIS3 Mutations. The Journal of clinical endocrinology and metabolism 59 26259131
2018 Discovery of a drug candidate for GLIS3-associated diabetes. Nature communications 54 29992946
2012 Sustained expression of the transcription factor GLIS3 is required for normal beta cell function in adults. EMBO molecular medicine 54 23197416
2011 Variants in GLIS3 and CRY2 are associated with type 2 diabetes and impaired fasting glucose in Chinese Hans. PloS one 52 21747906
2013 The Krüppel-like protein Gli-similar 3 (Glis3) functions as a key regulator of insulin transcription. Molecular endocrinology (Baltimore, Md.) 47 23927931
2016 Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes. Journal of molecular endocrinology 46 27899417
2011 The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice. Diabetologia 44 21786021
2020 Transcription factor GLIS3: Critical roles in thyroid hormone biosynthesis, hypothyroidism, pancreatic beta cells and diabetes. Pharmacology & therapeutics 35 32693112
2016 The Spatiotemporal Pattern of Glis3 Expression Indicates a Regulatory Function in Bipotent and Endocrine Progenitors during Early Pancreatic Development and in Beta, PP and Ductal Cells. PloS one 34 27270601
2017 The role of GLIS3 in thyroid disease as part of a multisystem disorder. Best practice & research. Clinical endocrinology & metabolism 33 28648506
2012 Glis3 regulates neurogenin 3 expression in pancreatic β-cells and interacts with its activator, Hnf6. Molecules and cells 32 22820919
2007 Krüppel-like zinc finger protein Glis3 promotes osteoblast differentiation by regulating FGF18 expression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 32 17488195
2019 PAX8-GLIS3 gene fusion is a pathognomonic genetic alteration of hyalinizing trabecular tumors of the thyroid. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 31 31273314
2016 Transcription Factor GLIS3: A New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis. Stem cells (Dayton, Ohio) 30 27350140
2018 A novel variant in GLIS3 is associated with osteoarthritis. Annals of the rheumatic diseases 29 29436472
2019 GLIS3 binds pancreatic beta cell regulatory regions alongside other islet transcription factors. The Journal of endocrinology 28 31340201
2011 Modulation of the transactivation function and stability of Krüppel-like zinc finger protein Gli-similar 3 (Glis3) by Suppressor of Fused. The Journal of biological chemistry 27 21543335
2018 Cryptotanshinone Protects Cartilage against Developing Osteoarthritis through the miR-106a-5p/GLIS3 Axis. Molecular therapy. Nucleic acids 26 29858052
2017 Molecular genetics of the transcription factor GLIS3 identifies its dual function in beta cells and neurons. Genomics 25 28911974
2015 HECT E3 Ubiquitin Ligase Itch Functions as a Novel Negative Regulator of Gli-Similar 3 (Glis3) Transcriptional Activity. PloS one 25 26147758
2014 TRANSCRIPTION FACTOR GLI-SIMILAR 3 (GLIS3): IMPLICATIONS FOR THE DEVELOPMENT OF CONGENITAL HYPOTHYROIDISM. Journal of endocrinology, diabetes & obesity 23 25133201
2009 Polycystic kidney disease in the medaka (Oryzias latipes) pc mutant caused by a mutation in the Gli-Similar3 (glis3) gene. PloS one 23 19609364
2018 GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors. Stem cells (Dayton, Ohio) 22 30376208
2021 Exosome-Mediated Transfer of circ-GLIS3 Enhances Temozolomide Resistance in Glioma Cells Through the miR-548m/MED31 Axis. Cancer biotherapy & radiopharmaceuticals 20 34762494
2017 Extended clinical features associated with novel Glis3 mutation: a case report. BMC endocrine disorders 20 28253873
2016 An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3). American journal of medical genetics. Part A 19 27148679
2021 GLIS3: A Critical Transcription Factor in Islet β-Cell Generation. Cells 18 34943978
2021 Case Report: Neonatal Diabetes Mellitus Caused by a Novel GLIS3 Mutation in Twins. Frontiers in endocrinology 17 34093443
2017 Differential Gene Dosage Effects of Diabetes-Associated Gene GLIS3 in Pancreatic β Cell Differentiation and Function. Endocrinology 17 27813676
2017 Mutation screening of the GLIS3 gene in a cohort of 592 Chinese patients with congenital hypothyroidism. Clinica chimica acta; international journal of clinical chemistry 17 29146476
2013 A low-frequency GLIS3 variant associated with resistance to Japanese type 1 diabetes. Biochemical and biophysical research communications 17 23856252
2022 GLIS3 mediated by the Rap1/PI3K/AKT signal pathway facilitates real-ambient PM2.5 exposure disturbed thyroid hormone homeostasis regulation. Ecotoxicology and environmental safety 15 35093813
2017 GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus. Acta diabetologica 15 28597135
2023 GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors. Cell & bioscience 13 36793061
2022 A circular RNA derived from GLIS3 accelerates the proliferation of glioblastoma cells through competitively binding with miR-449c-5p to upregulate CAPG and GLIS3. BMC neuroscience 13 36114444
2018 GLIS3 and Thyroid: A Pleiotropic Candidate Gene for Congenital Hypothyroidism. Frontiers in endocrinology 13 30555422
2022 Neonatal Diabetes, Congenital Hypothyroidism, and Congenital Glaucoma Coexistence: A Case of GLIS3 Mutation. Journal of clinical research in pediatric endocrinology 12 35410112
2020 Glis3 as a Critical Regulator of Thyroid Primordium Specification. Thyroid : official journal of the American Thyroid Association 12 31797737
2020 Oncogenic properties and signaling basis of the PAX8-GLIS3 fusion gene. International journal of cancer 12 32383186
2018 PIAS-family proteins negatively regulate Glis3 transactivation function through SUMO modification in pancreatic β cells. Heliyon 10 30094379
2024 GLIS3: A novel transcriptional regulator of mitochondrial functions and metabolic reprogramming in postnatal kidney and polycystic kidney disease. Molecular metabolism 9 39505148
2022 Case report: Neonatal diabetes mellitus with congenital hypothyroidism as a result of biallelic heterozygous mutations in GLIS3 gene. Pediatric diabetes 9 35394098
2015 4D MRI of polycystic kidneys from rapamycin-treated Glis3-deficient mice. NMR in biomedicine 9 25810360
2017 The Potential Role of Krüppel-Like Zinc-Finger Protein Glis3 in Genetic Diseases and Cancers. Archivum immunologiae et therapiae experimentalis 8 28523428
2023 circGlis3 promotes β-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein. iScience 6 38226164
2021 Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism. Molecular and cellular endocrinology 6 33667596
2020 Identification of a novel lncRNA (G3R1) regulated by GLIS3 in pancreatic β-cells. Journal of molecular endocrinology 6 32668405
2019 A GLIS3-CD133-WNT-signaling axis regulates the self-renewal of adult murine pancreatic progenitor-like cells in colonies and organoids. The Journal of biological chemistry 6 31533988
2024 Variations in the LINGO2 and GLIS3 Genes and Gene-Environment Interactions Increase Gestational Diabetes Mellitus Risk in Chinese Women. Environmental science & technology 5 38888423
2023 Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas. Diabetologia 5 38051360
2020 Association study of the functional variants of the GLIS3 gene with risk of knee osteoarthritis. Clinical rheumatology 5 32681364
2018 Polymorphism of the GLIS3 gene in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. BMC research notes 5 29606121
2024 A case of hyalinizing trabecular tumor of the thyroid: diagnostic significance of PAX8-GLIS3 fusion. Thyroid research 4 38705974
2022 Detection of a GLIS3 fusion in an infant with AML refractory to chemotherapy. Cold Spring Harbor molecular case studies 4 35927023
2018 Loss of Glis3 causes dysregulation of retrotransposon silencing and germ cell demise in fetal mouse testis. Scientific reports 4 29941866
2026 Bidirectional CRISPR screens decode a GLIS3-dependent fibrotic cell circuit. Nature 2 41501466
2025 Congenital glaucoma associated with high hyperopia, an ophthalmic phenotypical manifestation for GLIS3 deletion: case report and review of literature. Ophthalmic genetics 2 40583116
2024 FAM83H regulated by glis3 promotes triple-negative breast cancer tumorigenesis and activates the NF-κB signaling pathway. Journal of molecular histology 2 39304594
2012 Expression pattern of a single transgene cassette located in endogenous GLIS3 of cloned pigs; a nested situation. Gene 2 22555020
2025 Glis3 Is a Modifier of Cyst Progression in Autosomal Dominant Polycystic Kidney Disease. Journal of the American Society of Nephrology : JASN 1 41563804
2024 Downregulation of Glis3 in INS1 cells exposed to chronically elevated glucose contributes to glucotoxicity-associated β cell dysfunction. Islets 1 38652652
2023 Liver Disease in GLIS3 Mutations: Transplant Considerations and Bile Duct Paucity on Explant Histology. Journal of pediatric gastroenterology and nutrition 1 36917836
2017 GLIS3 and TYK2 Single Nucleotide Polymorphisms Are Not Associated with Dermatomyositis/Polymyositis in Chinese Han Population. Genetic testing and molecular biomarkers 1 28846454
2026 Identification of distinct functions of GLIS3 in β-cell generation critical to prevention of neonatal diabetes. bioRxiv : the preprint server for biology 0 41542538
2026 Case Report: Membranous/cytoplasmic Ki-67 staining and PAX8-GLIS3 fusion: defining the clinicopathological spectrum of hyalinizing trabecular tumor to optimize patient management. Frontiers in medicine 0 41778042
2026 Regulation of PKM2 expression and function by GLIS3 during metabolic reprogramming in polycystic kidneys. Experimental & molecular medicine 0 41826646
2026 GLIS3 is a key regulator of astrocyte differentiation in human neural stem cells. bioRxiv : the preprint server for biology 0 41959138
2026 Association of GCKR and GLIS3 gene polymorphisms with gestational diabetes mellitus: A case-control study. The Indian journal of medical research 0 42024906
2025 Hyalinizing trabecular tumor of the thyroid: Interest of GLIS3 immunohistochemical study to detect PAX8::GLIS3 rearrangement. Human pathology 0 40122401
2025 Glis3 is a modifier of cyst progression in autosomal dominant polycystic kidney disease. bioRxiv : the preprint server for biology 0 40661540
2025 GLIS3 rs7034200 and ADRB3 rs4994 genetic variants associated with an increased risk of gestational diabetes mellitus in Chinese women: a case-control study. BMC pregnancy and childbirth 0 41272565
2025 Alternative Splicing (AS) Provides an Alternative Mechanism for Regulating GLIS3 Expression and Activity. Cells 0 41369402
2025 Glis3 as a critical regulator of Pit1-lineages and renal functions. Journal of molecular medicine (Berlin, Germany) 0 41457180
2022 Gli-similar 3 (GLIS3) rs7020763 (C>G) polymorphism in patients with type 2 diabetes mellitus. The Egyptian journal of immunology 0 36206155