Affinage

GLIS3

Zinc finger protein GLIS3 · UniProt Q8NEA6

Length
775 aa
Mass
83.6 kDa
Annotated
2026-06-10
86 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GLIS3 is a Krüppel-like C2H2 zinc finger transcription factor that acts as both an activator and repressor of gene transcription, binding the high-affinity consensus (G/C)TGGGGGGT(A/C) through all five zinc fingers, with N- and C-terminal domains required for optimal transactivation and the fourth zinc finger essential for nuclear localization (PMID:14500813, PMID:18263616). It localizes to both the nucleus and the primary cilium (PMID:19273592). A central role is in pancreatic endocrine development and beta cell function: GLIS3 transactivates the Ngn3 promoter synergistically with HNF6 and FoxA2 to specify the endocrine lineage (PMID:21786021, PMID:22820919), and at the insulin promoter it acts as a pioneer-like factor that recruits CBP/p300 and remodels chromatin to scaffold stable assembly of Pdx1, MafA, and NeuroD1 complexes (PMID:19264802, PMID:23927931, PMID:38652652); loss of GLIS3 in mice causes neonatal diabetes through impaired islet development and reduced insulin expression (PMID:19481545, PMID:23197416). GLIS3 also drives thyroid development and hormone biosynthesis, acting downstream of TSH/TSHR to directly activate iodide-handling genes (Nis, Pds) within a regulatory hub shared with PAX8, NKX2.1, and FOXE1 (PMID:29083325, PMID:36793061). In the kidney GLIS3 is a positive regulator of mitochondrial biogenesis, OXPHOS, and fatty acid oxidation genes (Tfam, Ppargc1a/b) in coordination with HNF1B, and its loss reprograms metabolism toward aerobic glycolysis via Pkm/PKM2 dysregulation, contributing to cystogenesis (PMID:39505148, PMID:41826646, PMID:41563804). GLIS3 activity is tuned post-translationally: SUFU stabilizes it by antagonizing Cullin3-mediated ubiquitination (PMID:21543335), the HECT E3 ligase Itch drives its proteasomal degradation (PMID:26147758), and PIASy/Ubc9 SUMOylation inhibits its transactivation under chronic hyperglycemia (PMID:30094379). In humans, loss-of-function GLIS3 mutations cause a neonatal diabetes and congenital hypothyroidism syndrome (PMID:16715098).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2003 High

    Established GLIS3's fundamental molecular identity as a nuclear, GLI-related zinc finger transcription factor capable of bidirectional transcriptional control, defining the structural basis for all later functional work.

    Evidence Deletion mutant analysis and reporter assays on the nuclear protein

    PMID:14500813

    Open questions at the time
    • GLI-RE binding characterized only in vitro
    • physiological target genes not yet identified
  2. 2006 High

    Linked GLIS3 to human disease by showing loss-of-function mutations cause a neonatal diabetes/congenital hypothyroidism syndrome, establishing its in vivo importance for beta cell and thyroid development.

    Evidence Human mutation sequencing and in situ expression analysis across families

    PMID:16715098

    Open questions at the time
    • did not define direct target genes
    • molecular mechanism of beta cell/thyroid failure unresolved
  3. 2008 High

    Defined the optimal DNA-binding consensus and the domain requirements for DNA binding and nuclear import, and connected a patient frameshift mutation to loss of transactivation, mapping genotype to molecular defect.

    Evidence Zinc finger/NLS mutagenesis, EMSA, and reporter assays

    PMID:18263616

    Open questions at the time
    • consensus defined in vitro; genome-wide occupancy not yet mapped
  4. 2009 High

    Resolved how GLIS3 drives insulin transcription and endocrine specification, showing direct binding to the Ins2 promoter with Pdx1/MafA/NeuroD1, transactivation of Ngn3 with HNF6/FoxA2, and a requirement for islet development in knockout mice.

    Evidence ChIP, EMSA, co-IP, reporter assays, knockout mice, and ciliary/TAZ interaction studies

    PMID:19264802 PMID:19273592 PMID:19481545 PMID:21786021

    Open questions at the time
    • order of complex assembly at the insulin promoter not resolved
    • ciliary function of GLIS3 not mechanistically connected to transcription
  5. 2011 High

    Identified post-translational stabilization control, showing SUFU binds the GLIS3 N-terminal VYGHF motif and protects it from Cullin3-mediated degradation, revealing a layer of abundance regulation.

    Evidence Co-IP, motif mutagenesis, ubiquitination and protein stability assays

    PMID:21543335

    Open questions at the time
    • identity of the Cullin3 substrate adaptor not defined
    • upstream signals controlling SUFU-GLIS3 not established
  6. 2013 High

    Established GLIS3 as a scaffolding/pioneer-type factor at the insulin promoter and connected its loss to beta cell apoptosis through Bim splicing, explaining both transcriptional and survival consequences of GLIS3 deficiency.

    Evidence ChIP, co-IP, promoter mutagenesis, and siRNA/splicing analysis across multiple beta cell systems

    PMID:23737756 PMID:23927931

    Open questions at the time
    • mechanism linking GLIS3 to SRp55 regulation unknown
    • direct vs indirect control of apoptosis not fully separated
  7. 2015 High

    Identified Itch as an E3 ligase that degrades GLIS3 via a PPxY motif, complementing the SUFU stabilization axis and showing GLIS3 transactivation is governed by ubiquitin-dependent turnover.

    Evidence Mass spec, yeast two-hybrid, co-IP, mutagenesis, ubiquitination and degradation assays

    PMID:26147758

    Open questions at the time
    • signals regulating Itch-GLIS3 in beta cells unknown
    • interplay between Itch and Cullin3/SUFU pathways unresolved
  8. 2017 High

    Placed GLIS3 downstream of TSH/TSHR signaling in the thyroid, showing it directly activates iodide transporter genes and is required for follicular cell proliferation, defining its thyroid hormone biosynthesis role.

    Evidence ChIP-Seq, conditional KO mice, and mTORC1/RPS6 pathway analysis

    PMID:29083325

    Open questions at the time
    • how GLIS3 integrates with mTORC1 signaling mechanistically unresolved
  9. 2018 High

    Expanded GLIS3 targetome and lineage roles, identifying direct regulation of Slc2a2/MafA in beta cells, WNT genes in neural patterning, and piRNA/retrotransposon silencing in germ cells, plus SUMOylation as a hyperglycemia-responsive brake.

    Evidence ChIP-seq/RNA-seq, conditional and full KO mice, hESC differentiation, and SUMOylation assays

    PMID:29941866 PMID:29992946 PMID:30094379 PMID:30376208 PMID:31340201

    Open questions at the time
    • tissue-specific cofactors determining context-dependent target choice not defined
    • mechanism of GLIS3-driven retrotransposon silencing activation unknown
  10. 2019 High

    Defined GLIS3 oncogenic activity via the PAX8-GLIS3 fusion pathognomonic for hyalinizing trabecular tumors, and showed coordinate thyroid regulatory-hub binding with PAX8/NKX2.1/FOXE1, situating GLIS3 within thyroid developmental and tumor contexts.

    Evidence RNA-seq/FISH on tumor cohorts and progenitor knockdown plus thyroid ChIP-Seq integration

    PMID:31273314 PMID:31533988

    Open questions at the time
    • mechanism by which the fusion alters GLIS3 transcriptional output not fully defined at this stage
  11. 2020 Medium

    Connected GLIS3 (and the PAX8-GLIS3 fusion) functionally to Sonic Hedgehog signaling in thyroid fate determination and tumorigenesis, linking GLIS3 transcriptional output to a defined developmental pathway.

    Evidence Forced expression, xenografts, zebrafish morpholino knockdown, and pharmacological SHH/SMO inhibition

    PMID:31797737 PMID:32383186

    Open questions at the time
    • direct SHH pathway target genes of GLIS3 not enumerated
    • single-lab models for each system
  12. 2024 High

    Established GLIS3 as a master regulator of renal mitochondrial metabolism, showing direct activation of OXPHOS/FAO/biogenesis genes whose loss reprograms cells toward aerobic glycolysis and drives cystogenesis.

    Evidence Integrated transcriptomics, ChIP-Seq, metabolomics, Seahorse, and tissue-specific KO mice

    PMID:39505148

    Open questions at the time
    • coordination with NRF1/HNF1B at the molecular level not fully dissected
  13. 2025 High

    Mechanistically extended the renal metabolic and disease roles, identifying direct Pkm/PKM2 regulation with HNF1B, genetic interaction with Pkd1, and a novel fibroblast inflammatory/fibrotic program whose loss alleviates colitis, broadening GLIS3 into inflammation/fibrosis.

    Evidence ChIP-Seq, siRNA/PKM2 inhibition, allelic-series KO mice, genome-wide CRISPR screens, and single-cell/spatial profiling

    PMID:38652652 PMID:41501466 PMID:41563804 PMID:41826646

    Open questions at the time
    • fibroblast GRN cofactors not fully defined
    • how GLIS3 selects metabolic vs developmental programs across tissues unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how GLIS3 selects between activator and repressor functions and tissue-specific target sets, and how its ciliary localization mechanistically couples to its nuclear transcriptional roles.
  • no structural model of GLIS3 on DNA with cofactors
  • ciliary-to-nuclear signaling link uncharacterized
  • rules governing tissue-specific cofactor recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 8 GO:0140110 transcription regulator activity 8
Localization
GO:0005634 nucleus 2 GO:0005929 cilium 2
Pathway
R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-1430728 Metabolism 2
Partners
HNF6ITCHMAFANEUROD1PAX8PDX1SUFUWWTR1

Evidence

Reading pass · 35 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; the N- and C-termini are required for optimal transcriptional activity, and GLIS3 binds to the GLI-RE consensus sequence to enhance GLI-RE-dependent transcription. Deletion mutant analysis, reporter assays, nuclear protein characterization Nucleic acids research High 14500813
2006 Mutations in GLIS3 (frameshift and exon deletions) cause a neonatal diabetes/congenital hypothyroidism syndrome; GLIS3 is expressed in pancreatic beta cells from early developmental stages, establishing a major role in beta cell and thyroid development. Human genetic mutation identification (sequencing), in situ hybridization, transcript analysis Nature genetics High 16715098
2008 The tetrahedral configuration of the fourth zinc finger is essential for nuclear localization of Glis3 (the putative bipartite NLS is not required); the optimal high-affinity Glis3 DNA-binding site consensus is (G/C)TGGGGGGT(A/C); all five zinc finger motifs are critical for efficient DNA binding; the NDH1 patient frameshift mutation truncates the C-terminal transactivation domain, abolishing transactivating activity without affecting nuclear localization. Deletion/point mutagenesis, electrophoretic mobility shift assay, reporter assays, nuclear localization analysis Nucleic acids research High 18263616
2009 Glis3 localizes to the primary cilium and interacts with the transcriptional co-activator Wwtr1/TAZ; Wwtr1 recognizes a P/LPXY motif in the Glis3 C-terminus and enhances Glis3-mediated transcriptional activation; mutations in the P/LPXY motif abrogate Wwtr1 interaction and Glis3 transcriptional activity, defining this motif as part of the transactivation domain. Co-immunoprecipitation, mutagenesis, reporter assays, immunofluorescence/localization studies in Glis3 mutant mice Molecular and cellular biology High 19273592
2009 Glis3 directly binds the Ins2 promoter at a response element (5'-GTCCCCTGCTGTGAA-3' from -255 to -241) via its zinc finger region, and physically and functionally interacts with Pdx1, MafA, and NeuroD1 to modulate Ins2 promoter activity; Glis3 also indirectly affects insulin promoter activity by upregulating MafA and downregulating Nkx6-1. Chromatin immunoprecipitation, promoter deletion analysis, electrophoretic mobility shift assay, co-immunoprecipitation, siRNA knockdown, overexpression Nucleic acids research High 19264802
2009 Glis3-deficient mice develop neonatal diabetes due to impaired islet development and decreased insulin mRNA, establishing Glis3 as required for insulin-producing cell formation. Gene-targeting knockout mouse model, blood glucose measurement, mRNA expression analysis FEBS letters High 19481545
2011 GLIS3 directly transactivates the Neurogenin 3 (Ngn3) promoter through specific GLIS3-response elements; GLIS3 acts synergistically with HNF6 and FoxA2 to activate Ngn3 transcription, placing GLIS3 upstream of Ngn3 in the endocrine pancreas lineage specification pathway. In vivo Glis3 knockout analysis, ChIP, promoter reporter assays, in vitro reconstitution with transcription factors Diabetologia High 21786021
2011 Glis3 interacts directly with Hnf6 in vitro and in vivo; the amino-terminus of Glis3 and the homeodomain of Hnf6 are critical for this interaction; Glis3 binds to the distal Ngn3 promoter and activates Ngn3 transcriptional activity. Co-immunoprecipitation (in vivo and in vitro), deletion mutagenesis, promoter reporter assays, ChIP Molecules and cells High 22820919
2011 SUFU interacts with Glis3 via a VYGHF motif in the conserved N-terminal region of Glis3; SUFU inhibits Glis3-mediated insulin promoter activation in a manner dependent on their interaction; SUFU promotes nuclear accumulation of itself (driven by Glis3); SUFU stabilizes Glis3 by antagonizing a Cullin 3-based E3 ubiquitin ligase that promotes Glis3 ubiquitination and proteasomal degradation. Co-immunoprecipitation, mutagenesis (VYGHF motif), reporter assays, ubiquitination assay, protein stability analysis The Journal of biological chemistry High 21543335
2012 Sustained Glis3 expression in adult beta cells is required for normal beta cell function; Glis3 controls beta cell proliferation in response to high-fat feeding at least partly by regulating Ccnd2 transcription; conditional deletion of Glis3 in adult beta cells leads to downregulation of insulin expression, hyperglycemia, and enhanced beta cell apoptosis. Conditional knockout mouse (Glis3fl/fl/Pdx1CreERT+), tamoxifen-induced deletion, high-fat diet challenge, Ccnd2 promoter analysis EMBO molecular medicine High 23197416
2007 Glis3 promotes osteoblast differentiation in multipotent C3H10T1/2 cells, acts synergistically with BMP2 and Shh, and induces FGF18 expression through a Glis3 binding site in the FGF18 promoter; the C-terminal activation function of Glis3 is required for stimulation of osteoblast differentiation; Glis3 also inhibits adipocyte differentiation. Reporter assays, EMSA, microarray, alkaline phosphatase activity assay, overexpression in C3H10T1/2 cells Journal of bone and mineral research Medium 17488195
2013 Glis3 recruits CBP/p300 to form a scaffold for the transcriptional regulatory complex at the insulin promoter; Glis3 binding to GlisBS is required for stable association of Pdx1, NeuroD1, and MafA with their respective binding sites in the insulin promoter; mutations in GlisBS abrogate activation by all three co-regulators; a naturally occurring GlisBS mutation associated with neonatal diabetes reduces the insulin promoter activity. ChIP, co-immunoprecipitation, reporter assays, siRNA knockdown, promoter mutagenesis Molecular endocrinology (Baltimore, Md.) High 23927931
2013 GLIS3 knockdown in beta cells increases apoptosis via the intrinsic mitochondrial pathway (cytochrome c release, Bax mitochondrial translocation, caspase 9/3 activation) by modulating alternative splicing of the pro-apoptotic protein Bim, favoring expression of the pro-death BimS variant through inhibition of the splicing factor SRp55; knockdown of Bim abrogates the pro-apoptotic effect of GLIS3 loss. siRNA knockdown in INS-1E cells, primary rat beta cells, and human islets; apoptosis assays (cytochrome c, caspase activation); RT-PCR splicing analysis; epistasis with Bim knockdown PLoS genetics High 23737756
2015 The HECT E3 ubiquitin ligase Itch interacts with Glis3 through its WW-domains binding a PPxY motif in the Glis3 N-terminus; Itch promotes Glis3 polyubiquitination and proteasomal degradation, requiring both the PPxY motif interaction and the zinc finger domains; Itch dramatically inhibits Glis3-mediated transactivation and endogenous Ins2 expression by increasing Glis3 protein turnover. Mass spectrometry, yeast 2-hybrid, co-immunoprecipitation, mutation analysis, ubiquitination assay, proteasomal degradation assay, reporter assays PloS one High 26147758
2016 GLIS3 is expressed in gonocytes, spermatogonial stem cells (SSCs), and spermatogonial progenitors in the testis; loss of GLIS3 function impairs generation of SSCs/SPCs, causes aberrant cytoplasmic-to-nuclear FOXO1 translocation (blocking the gonocyte-to-SSC transition), and greatly impairs spermatogenesis. GLIS3 knockout mice, gene expression profiling, immunohistochemistry, FOXO1 localization analysis Stem cells (Dayton, Ohio) Medium 27350140
2017 GLIS3 acts downstream of TSH/TSHR signaling and is indispensable for TSH/TSHR-mediated proliferation of thyroid follicular cells and thyroid hormone biosynthesis; GLIS3 directly activates transcription of iodide transporters Nis and Pds (shown by enhanced GLIS3 binding at their promoters by ChIP-Seq); GLIS3 deficiency inhibits TSH-mediated mTORC1/RPS6 pathway activation and reduces expression of cell division-related genes directly regulated by GLIS3. ChIP-Seq, promoter analysis, conditional knockout mouse, pathway analysis (mTORC1/RPS6), thyroid follicular cell culture The Journal of clinical investigation High 29083325
2018 PIASy and Ubc9 SUMOylate Glis3 at two conserved lysine residues in the N-terminus; SUMO modification of Glis3 dramatically inhibits insulin transcription; Glis3 SUMOylation increases under conditions of chronically elevated glucose, correlating with decreased insulin transcription. SUMOylation assay, mutagenesis of SUMO acceptor lysines, reporter assays, co-immunoprecipitation, glucose treatment experiments Heliyon Medium 30094379
2018 Loss of GLIS3 in pancreatic progenitors causes beta cell death by activating the TGFβ pathway; a drug candidate identified by high-content chemical screen rescues mutant GLIS3-associated beta cell death both in vitro and in vivo. GLIS3-/- hESC differentiation platform, high-content chemical screen, in vitro and in vivo rescue experiments, TGFβ pathway analysis Nature communications Medium 29992946
2018 GLIS3 directly regulates transcription of several genes critical for beta cell function, including Slc2a2 (Glut2) and Mafa, as revealed by GLIS3 ChIP-seq binding near these genes coinciding with binding of other islet-enriched transcription factors; pancreas-specific Glis3 deletion causes beta cells to persist as PDX1+/INS-/MAFA-/GLUT2- cells without increased cell death. Pancreas-specific Glis3 conditional KO (Pdx1-Cre), islet RNA-seq, GLIS3 ChIP-seq, immunohistochemistry The Journal of endocrinology Medium 31340201
2018 GLIS3 directly regulates transcription of several WNT genes, including WNT3A, to direct differentiation of hESCs toward posterior neural progenitor cells; inhibition of WNT signaling abrogates GLIS3-induced posterior specification. RNA-Seq, ChIP-Seq, functional reporter assays, WNT pathway inhibition, hESC differentiation Stem cells (Dayton, Ohio) Medium 30376208
2018 Loss of GLIS3 function leads to widespread reduction in retrotransposon silencing factors, aberrant retrotransposon expression, and germ cell loss in fetal testis; precocious induction of GLIS3 results in premature expression of piRNA pathway members, establishing GLIS3 as necessary for activation of retrotransposon silencing programs. GLIS3 knockout mice, gene expression profiling, inducible GLIS3 expression in vivo Scientific reports Medium 29941866
2019 GLIS3 directly regulates self-renewal of adult murine pancreatic progenitor-like cells (PCFUs) through a GLIS3-to-CD133-to-WNT signaling axis; GLIS3 and CD133 maintain WNT receptors and signaling molecules allowing responses to WNT ligands; CD133, but not GLIS3 or WNT, is required for PI3K/AKT-mediated PCFU survival. shRNA knockdown in sorted pancreatic progenitor cells, colony/organoid assay, gene and protein expression analysis The Journal of biological chemistry Medium 31533988
2019 PAX8-GLIS3 in-frame gene fusion (PAX8 exons 1-2 fused to GLIS3 exons 3-11) is a pathognomonic genetic alteration present in 100% of hyalinizing trabecular tumors of the thyroid and absent in 237 control thyroid neoplasms. RNA sequencing, RT-PCR, FISH, targeted massively parallel sequencing Modern pathology High 31273314
2020 The PAX8-GLIS3 fusion protein 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; pharmacological inhibition of SMO partially reverses increased proliferation, colony formation, and migration. Forced expression, xenograft, cell proliferation/migration assays, SMO inhibitor (Cyclopamine) treatment, GLI reporter assays International journal of cancer Medium 32383186
2020 Glis3, acting within the SHH pathway as an effector, determines the number of endodermal cells committed to thyroid fate in zebrafish; glis3 morphants show reduced expression of early thyroid transcription factors nkx2.4 and pax2a at the thyroid primordium; molecular and pharmacological inhibition of SHH reproduces thyroid defects observed in glis3 morphants. Morpholino knockdown in zebrafish, in situ hybridization, immunohistochemistry, pharmacological SHH inhibition, rescue experiments Thyroid Medium 31797737
2023 GLIS3 regulates transcription of thyroid hormone biosynthetic genes (including Slc5a5/Nis, Slc26a4, Cdh16, Adm2) in coordination with PAX8, NKX2.1, and FOXE1 by binding within the same regulatory hub; loss of GLIS3 does not significantly affect PAX8 or NKX2.1 binding and does not cause major alterations in H3K4me3 and H3K27me3 epigenetic signals. ChIP-Seq (PAX8, NKX2.1, FOXE1, GLIS3), ChIP-QPCR, Glis3 KO mouse thyroid analysis, chromatin state analysis Cell & bioscience High 36793061
2024 GLIS3 is a positive regulator of mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), fatty acid oxidation, and TCA cycle gene expression in postnatal kidney; ChIP-Seq shows direct GLIS3 binding at regulatory regions of genes including Tfam, Tfb1m, Ppargc1a, Ppargc1b; loss of GLIS3 leads to metabolic reprogramming with increased aerobic glycolysis and glutamine anaplerosis contributing to renal cyst formation. Transcriptomics, ChIP-Seq, metabolomics, Seahorse analysis, tissue-specific Glis3 KO mice Molecular metabolism High 39505148
2024 Glis3 is downregulated transcriptionally in beta cells exposed to chronically elevated glucose due at least partly to increased oxidative stress; reduced Glis3 expression decreases insulin and MafA expression, upregulates beta cell disallowed genes; Glis3 acts similarly to a pioneer factor at the insulin promoter by permissively remodeling chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA; Glis3 can positively regulate MafA transcription through its pancreas-specific promoter, and MafA reciprocally regulates Glis3 expression. CRISPR/Cas9 knockdown, high glucose treatment, chromatin accessibility analysis, reporter assays, gene expression analysis Islets Medium 38652652
2025 GLIS3 directly regulates a gene regulatory network governing expression of inflammatory and fibrotic genes in intestinal inflammation-associated fibroblasts; fibroblast-specific deletion of Glis3 in mice alleviates pathological features of chronic colitis; GLIS3 acts as a key regulator in a fibroblast activation program induced by proinflammatory macrophages. Genome-wide CRISPR KO and activation screens, single-cell and spatial profiling, conditional fibroblast-specific Glis3 KO mice in colitis model Nature High 41501466
2025 GLIS3 directly regulates Pkm expression and through this controls PKM2 isoform levels and metabolic reprogramming in polycystic kidneys; GLIS3 regulates glycolytic gene expression in coordination with HNF-1B; exogenous GLIS3 suppresses Pkm expression in primary Glis3-KO renal epithelial cells; pharmacological inhibition of PKM2 reduces spheroid size and cystogenesis in GLIS3-deficient models. Transcriptomics, ChIP-Seq, siRNA knockdown, exogenous GLIS3 expression, pharmacological PKM2 inhibition, in vivo Glis3-KO kidney analysis Experimental & molecular medicine High 41826646
2025 Alternative splicing of Glis3 generates a shorter mouse mRNA lacking exon 3 that produces a 659 aa protein more stable and with greater transactivation potential than the full-length 935 aa protein; mass spectrometry identified phosphorylation sites and co-activator/co-repressor complex members that interact with GLIS3. RT-PCR, splice variant cloning, reporter assays, protein stability analysis, mass spectrometry Cells Medium 41369402
2025 Glis3 ciliary localization is not affected by Pkd1 mutation status; kidney-selective dual inactivation of Glis3 and Pkd1 significantly worsens polycystic kidney disease compared to Pkd1 inactivation alone, establishing genetic interaction; Glis3 inactivation dysregulates fatty acid metabolism and circadian regulation, with GLIS3 functioning in a transcriptional network with HNF1B, HNF4A, and DBP. Live cell confocal imaging, conditional KO mice (allelic series), RNA-Seq, ATAC-Seq Journal of the American Society of Nephrology High 41563804
2026 GLIS3 transcriptionally activates TGFBR3 expression (confirmed by ChIP-qPCR and dual-luciferase assay), which in turn activates the Hedgehog pathway to promote EMT and cancer stem cell-like traits in stomach adenocarcinoma; bidirectional rescue experiments confirm functional dependency on TGFBR3. ChIP-qPCR, dual-luciferase reporter assay, co-immunoprecipitation, GLI reporter assays, gain/loss-of-function, xenograft Frontiers in oncology Medium 42255230
2026 GLIS3 is highly expressed in astrocytes and is required for efficient differentiation of human neural progenitor cells (NPCs) into astrocytes; GLIS3 directly regulates transcription of astrocyte-associated genes including GFAP, SLC1A2, NFIA, and ATF3 in coordination with STAT3, NFIA, and SOX9. GLIS3 loss-of-function, exogenous GLIS3 expression, transcriptomics (RNA-Seq), ChIP-Seq, NPC differentiation assay bioRxivpreprint Medium 41959138
2026 GLIS3 regulates two distinct stages of pancreatic development: embryonic generation/differentiation of bipotent progenitor cells and the differentiation of preβ to β cells; loss of GLIS3 generates a unique subpopulation of cells that fail to upregulate Ins2 and fail to downregulate ribosomal and oxidative phosphorylation genes normally repressed during preβ to β cell differentiation. Single-cell RNA-seq at e13.5, e15.5, e18.5 in WT vs Glis3 KO embryos; snATAC-seq at e15.5 bioRxivpreprint Medium 41542538

Source papers

Stage 0 corpus · 86 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 109 14500813
2009 Glis3 is associated with primary cilia and Wwtr1/TAZ and implicated in polycystic kidney disease. Molecular and cellular biology 89 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 63 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 55 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 38 32693112
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 35 31273314
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 33 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 GLIS3 binds pancreatic beta cell regulatory regions alongside other islet transcription factors. The Journal of endocrinology 30 31340201
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
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 26 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 24 25133201
2018 GLIS3 Transcriptionally Activates WNT Genes to Promote Differentiation of Human Embryonic Stem Cells into Posterior Neural Progenitors. Stem cells (Dayton, Ohio) 23 30376208
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
2021 Exosome-Mediated Transfer of circ-GLIS3 Enhances Temozolomide Resistance in Glioma Cells Through the miR-548m/MED31 Axis. Cancer biotherapy & radiopharmaceuticals 21 34762494
2017 Extended clinical features associated with novel Glis3 mutation: a case report. BMC endocrine disorders 20 28253873
2021 GLIS3: A Critical Transcription Factor in Islet β-Cell Generation. Cells 19 34943978
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 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 16 35093813
2023 GLIS3 regulates transcription of thyroid hormone biosynthetic genes in coordination with other thyroid transcription factors. Cell & bioscience 15 36793061
2017 GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus. Acta diabetologica 15 28597135
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 14 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
2024 Variations in the LINGO2 and GLIS3 Genes and Gene-Environment Interactions Increase Gestational Diabetes Mellitus Risk in Chinese Women. Environmental science & technology 7 38888423
2024 A case of hyalinizing trabecular tumor of the thyroid: diagnostic significance of PAX8-GLIS3 fusion. Thyroid research 6 38705974
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
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
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 3 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 Hyalinizing trabecular tumor of the thyroid: Interest of GLIS3 immunohistochemical study to detect PAX8::GLIS3 rearrangement. Human pathology 1 40122401
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 1 41272565
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
2022 Gli-similar 3 (GLIS3) rs7020763 (C>G) polymorphism in patients with type 2 diabetes mellitus. The Egyptian journal of immunology 1 36206155
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
2026 GLIS3 marks a neural-like progenitor cell state that drives metastasis in pancreatic ductal adenocarcinoma. Cell reports 0 42048185
2026 GLIS3 drives epithelial-mesenchymal transition and cancer stem-like traits in stomach adenocarcinoma via TGFBR3-Hedgehog signaling. Frontiers in oncology 0 42255230
2025 Glis3 is a modifier of cyst progression in autosomal dominant polycystic kidney disease. bioRxiv : the preprint server for biology 0 40661540
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

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