Affinage

GRHL3

Grainyhead-like protein 3 homolog · UniProt Q8TE85

Length
626 aa
Mass
70.3 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRHL3 is an epithelial transcription factor and a member of the grainyhead family that acts as a master regulator of surface epithelium commitment, epidermal differentiation, and epithelial barrier integrity (PMID:12549979, PMID:19521564, PMID:35857527). It is sufficient to initiate surface ectoderm fate from pluripotent cells by priming chromatin accessibility, activating surface-epithelium genes, and establishing a positive feedback loop with BMP4, and it acts downstream of canonical Wnt signaling to specify the neural plate border surface ectoderm required for neural tube closure (PMID:26288816, PMID:35857527). As a differentiation regulator GRHL3 directly binds and activates terminal differentiation and barrier targets including Transglutaminase 1, uroplakin II in urothelium, and APOBEC3A in terminally differentiating keratinocytes (PMID:19521564, PMID:19494835, PMID:39548236), while simultaneously restraining stem/progenitor and proliferative programs by suppressing Wnt signaling and controlling the stem-to-transition cell transition (PMID:33116143). It executes these programs through dynamic enhancer/promoter usage and chromatin remodeling, recruiting Trithorax complex members to activate differentiation genes and binding super-enhancers in differentiating cells versus promoters (with REST) during migration (PMID:22829784, PMID:28445475). GRHL3 functions as a tumor suppressor: it directly activates PTEN to restrain PI3K/AKT/mTOR signaling, and its loss in epidermis drives squamous cell carcinoma rescuable by PTEN restoration, while it also represses the miR-21 oncomiR and activates HOPX to limit Wnt/β-catenin in esophageal carcinoma (PMID:22094257, PMID:22614019, PMID:36442813). During wound repair GRHL3 cooperates genetically and biochemically with the LIM-only protein LMO4 and acts upstream of TGFα in the EGFR/ERK pathway to drive actin-based keratinocyte migration, and activates FSCN1 to loosen adherens junctions for collective migration (PMID:16949565, PMID:18485343, PMID:18619436, PMID:34494554). Coding mutations in GRHL3 cause Van der Woude syndrome, and GRHL3 acts in a TFAP2A-IRF6 regulatory pathway during palatogenesis and neurulation (PMID:24360809, PMID:30689861). GRHL3 abundance is itself controlled post-transcriptionally in progenitors through CPSF-HNRNPA3-mediated intronic polyadenylation that suppresses full-length transcript to prevent premature differentiation (PMID:33469008).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2003 Medium

    Establishing GRHL3 as a grainyhead-family transcription factor that selectively heterodimerizes defined the molecular class and partner specificity underlying its activity.

    Evidence Protein interaction pulldowns and domain/phylogenetic analysis across isoforms

    PMID:12549979

    Open questions at the time
    • No direct DNA target or functional consequence of dimerization shown
    • Dimerization assayed in vitro without in vivo confirmation
  2. 2003 High

    Identifying Grhl3 as the gene underlying the curly tail phenotype tied the transcription factor to neural tube closure and distinguished its defects from folate/inositol-responsive ones.

    Evidence Knockout mice, genetic complementation, and mapping

    PMID:14608380

    Open questions at the time
    • Direct transcriptional targets in neural tube not identified here
    • Mechanism of closure failure unresolved at the molecular level
  3. 2005 Medium

    Linking Grhl3 loss to barrier failure via Transglutaminase 1 provided the first direct differentiation target and a mechanistic basis for the skin phenotype.

    Evidence Null mice, expression analysis, ultrastructural lipid analysis

    PMID:19521564

    Open questions at the time
    • Direct promoter binding to TGase1 not demonstrated in this study
    • Single lab
  4. 2006 High

    Demonstrating biochemical and genetic interaction with LMO4 revealed that GRHL3 acts in a cofactor complex to drive epidermal terminal differentiation.

    Evidence Co-IP and double-knockout mouse genetics with barrier assays

    PMID:16949565

    Open questions at the time
    • Structural basis of GRHL3-LMO4 interaction unknown
    • Whether LMO4 alters target-gene selection not defined
  5. 2008 High

    Placing Get1/Grhl3 upstream of TGFα in the EGFR/ERK pathway and showing LMO4-dependent ERK activation connected GRHL3 to actin-driven keratinocyte migration during eyelid closure and wound repair.

    Evidence Knockout mice (eye-open), organ culture, phospho-EGFR/ERK westerns, TGFα rescue, scratch assays

    PMID:18485343 PMID:18619436

    Open questions at the time
    • Direct transcriptional target driving TGFα/ERK not pinpointed
    • Cytoskeletal effectors downstream not fully mapped
  6. 2009 High

    ChIP evidence that uroplakin II is a direct Get1 target extended GRHL3's barrier role beyond skin to urothelial differentiation and demonstrated direct promoter binding.

    Evidence Knockout mice, expression profiling, ChIP, reporter assays

    PMID:19494835

    Open questions at the time
    • Histone-modification context of selective binding only partially defined
    • Cofactor requirements at the uroplakin promoter unclear
  7. 2011 High

    Identifying PTEN as a direct GRHL3 target whose restoration abrogates SCC established GRHL3 as a tumor suppressor restraining PI3K/AKT/mTOR signaling.

    Evidence Conditional knockout, ChIP, Pten genetic rescue, tumor assays

    PMID:22094257

    Open questions at the time
    • Whether other GRHL3 targets contribute to SCC suppression not resolved here
  8. 2011 Medium

    Showing GRHL3 drives endothelial Akt/eNOS phosphorylation for NO-dependent migration and anti-apoptosis broadened its role beyond epithelium.

    Evidence siRNA knockdown in endothelial cells, migration/apoptosis assays, phospho-westerns

    PMID:21856281

    Open questions at the time
    • Direct transcriptional targets in endothelium not identified
    • siRNA only, single lab
  9. 2012 High

    Defining direct miR-21 promoter repression (with downstream MSH2/DND1 effects) and Trithorax recruitment clarified how GRHL3 both represses oncogenic programs and epigenetically activates differentiation genes.

    Evidence ChIP/luciferase for miR-21, miRNA profiling, xenografts; ChIP-seq and expression profiling for Trithorax recruitment

    PMID:22614019 PMID:22829784

    Open questions at the time
    • Mechanism of Trithorax complex recruitment to GRHL3 sites not defined
    • How GRHL3 switches between activation and repression unresolved
  10. 2013 High

    Linking GRHL3 coding mutations to Van der Woude syndrome with dominant-negative periderm defects, and finding no IRF6 epistasis, established GRHL3 as a human cleft-palate gene acting in a pathway convergent with but separate from IRF6.

    Evidence VWS family sequencing, zebrafish functional assay, mouse double-heterozygote epistasis

    PMID:24360809

    Open questions at the time
    • Periderm target genes of GRHL3 not identified
    • Penetrance determinants of cleft palate unexplained
  11. 2014 High

    ChIP-Seq across development versus repair showed GRHL3 deploys distinct target sets contextually and suppresses alarmin/proinflammatory genes after injury, defining a stage-specific regulatory logic.

    Evidence Conditional knockout, imiquimod model, ChIP-Seq, expression profiling

    PMID:25347468

    Open questions at the time
    • Determinants of context-specific binding not defined
    • Cofactors distinguishing development vs repair targets unknown
  12. 2015 Medium

    Placing Grhl3 downstream of canonical Wnt/DKK1/KREMEN1 for surface ectoderm specification, and within a leptin/miR-21/Grhl3/NOS3 axis in NASH endothelium, connected upstream signaling to GRHL3-dependent fate and vascular function.

    Evidence Wnt pathway manipulation with expression profiling; rodent NASH and leptin-null models with westerns/qRT-PCR

    PMID:25658689 PMID:26288816

    Open questions at the time
    • Direct Wnt-responsive elements controlling Grhl3 not mapped
    • Causal vs correlative role in NASH endothelium not fully separated
  13. 2017 High

    Genome-wide chromatin profiling revealed dynamic GRHL3 enhancer/promoter rearrangement between cell states and BRD4/FOXO1-dependent control of its own expression, explaining state-specific output and upstream regulation.

    Evidence GRHL3 and H3K27ac ChIP-seq, ATAC-seq in keratinocyte states; BRD4 ChIP-seq with EGFR/AKT/Src inhibitors

    PMID:27980063 PMID:28445475

    Open questions at the time
    • Mechanism redirecting GRHL3 to super-enhancers vs promoters unknown
    • Functional cooperation with REST during migration only partially defined
  14. 2018 Medium

    Discovering cytoplasmic GRHL3 controlling membrane VANGL2/CELSR1 and a TARC/CCL17-driven hyperproliferation phenotype expanded GRHL3 function to planar-cell-polarity mechanics and inflammatory suppression.

    Evidence Embryoid body differentiation with subcellular imaging; siRNA knockdown, cytokine array, KO mouse immunophenotyping, 5-ASA rescue

    PMID:30283008 PMID:30341279

    Open questions at the time
    • Mechanism of GRHL3 cytoplasmic relocalization unknown
    • Whether TARC regulation is direct not established
  15. 2019 Medium

    Genetic epistasis placing Irf6 upstream of Grhl3 (within a TFAP2A-IRF6-GRHL3 pathway) in neurulation defined the transcriptional hierarchy controlling GRHL3 expression in neural tube closure.

    Evidence Irf6 gain- and loss-of-function mice, expression analysis, human spina bifida sequencing

    PMID:30689861

    Open questions at the time
    • Direct regulatory connections among TFAP2A, IRF6, and GRHL3 not shown
    • Single lab
  16. 2020 High

    Single-cell analysis showed GRHL3 governs the gradual stem-to-transition cell switch and suppresses Wnt in stem cells, refining its role from a terminal-differentiation activator to a regulator of progenitor exit.

    Evidence scRNA-seq with RNA velocity and conditional knockout mice

    PMID:33116143

    Open questions at the time
    • Direct Wnt-pathway targets in stem cells not identified
    • Switch-controlling cofactors undefined
  17. 2021 High

    Defining GRHL3-driven FSCN1 activation (lowering E-cadherin for collective migration), zebrafish E-cadherin/cell-adhesion control, and CPSF-HNRNPA3 intronic polyadenylation of GRHL3 itself clarified both how GRHL3 controls epithelial mechanics and how progenitors restrain its expression.

    Evidence Conditional KO + ATAC-seq + wound assays (FSCN1); zebrafish live imaging/genetics; CRISPR IpA-site knockout, CPSF knockdown, RNA-seq, protein interaction

    PMID:33469008 PMID:34494554 PMID:34570762

    Open questions at the time
    • How HNRNPA3 directs CPSF specifically to the GRHL3 intron not fully resolved
    • Signals triggering the IpA switch during differentiation unknown
  18. 2022 High

    Demonstrating GRHL3 sufficiency to initiate surface-epithelium fate (priming chromatin, BMP4 feedback) and direct HOPX activation limiting Wnt/β-catenin in ESCC unified its roles in fate commitment and tumor suppression.

    Evidence hESC differentiation with Hi-C/ATAC-seq/ChIP-seq/RNA-seq and overexpression; conditional KO with ChIP-seq/ChIP-PCR and patient samples

    PMID:35857527 PMID:36442813

    Open questions at the time
    • Pioneer-factor mechanism of chromatin priming not mechanistically dissected
    • How GRHL3 activity is restrained in carcinoma cells unclear
  19. 2024 Medium

    Identifying direct activation of APOBEC3A and a GRHL3/lnc-DC/ZNF750 axis, plus GPX4-mediated nuclear silencing of GRHL3 in HCC, extended GRHL3 control to mutagenic enzymes, lncRNA-RNA-binding-protein circuits, and a new mode of transcriptional repression in cancer.

    Evidence scRNA-seq/spatial transcriptomics + functional keratinocyte experiments (APOBEC3A); CUT&RUN/RIP/RNA-stability assays (lnc-DC/ZNF750); GPX4 overexpression, nuclear fractionation, promoter binding, metastasis assays

    PMID:38383230 PMID:38797432 PMID:39548236

    Open questions at the time
    • Consequence of expanded APOBEC3A expression to proliferating SCC cells not fully tested
    • Mechanism by which nuclear GPX4 silences the GRHL3 promoter incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRHL3 selects context-specific target sets and switches between gene activation and repression across cell states remains the central unresolved mechanistic question.
  • No unifying model for activation vs repression switching
  • Determinants of dynamic enhancer/promoter and super-enhancer redistribution undefined
  • Mechanism and signals controlling cytoplasmic vs nuclear GRHL3 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 5
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3
Partners
GRHL1GRHL2LMO4REST

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 GRHL3 (SOM) was identified as a developmental transcription factor that is a mammalian homolog of Drosophila grainyhead; protein interaction studies demonstrated that SOM can heterodimerize with MGR (GRHL1) and Brother-of-MGR (GRHL2), but not with more distant family members, via conserved protein dimerization domains. Protein interaction studies (pulldown/co-IP), phylogenetic and domain analysis, alternative splicing characterization The Biochemical journal Medium 12549979
2003 Grhl3-null mice develop severe neural tube defects (spina bifida and anencephaly) that are folate-resistant and, unlike in the hypomorphic curly tail (ct/ct) strain, also inositol-resistant; gene targeting, mapping, and genetic complementation established Grhl3 as the gene underlying the curly tail phenotype. Gene targeting (knockout mice), genetic complementation, mapping studies Nature medicine High 14608380
2005 Grhl3 regulates epidermal barrier formation by controlling Transglutaminase 1 (TGase 1) expression as a direct target gene; Grhl3-null mice fail to form adequate skin barrier and exhibit defective extracellular lipid processing, altered lamellar lipid architecture, and cellular hyperproliferation. Gene knockout (null mice), gene expression analysis, ultrastructural analysis Organogenesis Medium 19521564
2006 GRHL3/Get-1 interacts with the LIM-only protein LMO4 in the developing epidermis; Get-1(-/-) mice show severe barrier defects, and double deletion of Get-1 and LMO4 produces a more severe epidermal terminal differentiation defect than either single knockout, demonstrating functional interaction between the two factors. Protein interaction (co-IP), genetic interaction (double knockout mice), barrier function assays, histology Developmental biology High 16949565
2008 Get1/Grhl3 promotes F-actin polymerization, filopodia formation, and cell shape changes required for keratinocyte migration at the leading edge during eyelid closure; Get1(-/-) mice have eye-open-at-birth phenotype associated with decreased TGFα expression and reduced phospho-EGFR and phospho-ERK at the leading edge, placing Get1 upstream of TGFα in the EGFR/ERK pathway. Knockout mice (eye-open phenotype), organ culture, immunofluorescence, western blot (phospho-EGFR, phospho-ERK), TGFα rescue experiment Developmental biology High 18485343
2008 GRHL3 and LMO4 interact biochemically and genetically; double knockout (Grhl3(-/-)/Lmo4(-/-)) mice exhibit fully penetrant exencephaly, spina bifida, barrier defects, and eye-open-at-birth phenotype not seen in either single null. ERK1/2 phosphorylation is lost in double-null epidermis and keratinocytes fail wound healing in scratch assays dependent on ERK activation and actin cable formation. Biochemical interaction (co-IP), double knockout mouse genetics, in vitro scratch assay, immunofluorescence, western blot Developmental biology High 18619436
2009 Get1/Grhl3 regulates urothelial differentiation and bladder barrier formation; Get1(-/-) mice show defective apical membrane specialization in bladder umbrella cells with downregulation of uroplakins, and uroplakin II is a direct transcriptional target of Get1, with selective binding to the uroplakin II promoter in urothelial cells regulated by histone modifications. Knockout mice, genome-wide expression profiling, ChIP (direct promoter binding), reporter assay The EMBO journal High 19494835
2011 Deletion of Grhl3 in adult mouse epidermis leads to loss of PTEN expression and aggressive squamous cell carcinoma (SCC) driven by PI3K/AKT/mTOR activation; PTEN is a direct GRHL3 transcriptional target, and restoration of Pten expression completely abrogates SCC formation. Conditional knockout mice, ChIP (PTEN as direct target), Pten rescue experiment, tumor assays Cancer cell High 22094257
2011 GRHL3 functions in endothelial cells to promote migration and inhibit apoptosis via induction of Akt and eNOS phosphorylation; nitric oxide (NO)-dependent migration is completely dependent on GRHL3 expression, and GRHL3 inhibits apoptosis in an eNOS-dependent manner. siRNA knockdown in endothelial cells, migration assay, apoptosis assay, western blot (phospho-Akt, phospho-eNOS) Biochemical and biophysical research communications Medium 21856281
2012 GRHL3/GET1 suppresses miR-21 expression by directly binding and repressing the miR-21 promoter; in Grhl3-deleted skin and transformed keratinocytes, elevated miR-21 downregulates the tumor suppressor MSH2, with enhanced effect mediated by loss of the RNA-binding protein DND1 during oncogenic transformation. miRNA profiling, ChIP (miR-21 promoter binding by GRHL3), luciferase reporter assay, overexpression/knockdown in keratinocytes, tumor xenograft assay Oncogene High 22614019
2012 GRHL3/GET1 recruits the ubiquitously expressed Trithorax complex to a subset of epidermal differentiation genes; GRHL3 collaborates with Trithorax group members to activate the epidermal progenitor differentiation program, both for genes repressed by Polycomb and genes independent of Polycomb regulation. ChIP-seq, gene expression profiling, genome-wide analysis in epidermis PLoS genetics Medium 22829784
2013 Coding mutations in GRHL3 cause Van der Woude syndrome (VWS); zebrafish assay showed that disease-associated GRHL3 mutations abrogate periderm development with a dominant-negative effect; in mice, all Grhl3-null embryos exhibit abnormal oral periderm and 17% develop cleft palate. Epistasis analysis of Irf6(+/-);Grhl3(+/-) double heterozygotes found no epistasis, indicating IRF6 and GRHL3 function in separate but convergent pathways during palatogenesis. Sequencing of VWS families, zebrafish functional assay, mouse knockout/double heterozygote genetic epistasis American journal of human genetics High 24360809
2014 GRHL3 is required for barrier repair after adult epidermal injury but dispensable for adult skin homeostasis; in an imiquimod-induced immune-mediated hyperplasia model, GRHL3-deficient mice have exacerbated damage response. ChIP-Seq revealed that GRHL3 targets distinct gene sets during development versus repair, and suppresses alarmin and proinflammatory genes after immune injury. Conditional knockout mice, imiquimod model, ChIP-Seq, gene expression profiling The Journal of clinical investigation High 25347468
2015 Grhl3 transcriptionally activates PTEN expression in endothelial sinusoids; leptin-induced upregulation of miR-21 targets and represses Grhl3, leading to decreased NOS3 phosphorylation and sinusoidal endothelial dysfunction in NASH. Loss of leptin or its receptor reverses miR-21 upregulation and restores Grhl3 and NOS3-p/NOS3 levels. Rodent NASH models, transgenic mice (leptin/leptin receptor null), western blot, qRT-PCR, immunofluorescence PloS one Medium 25658689
2015 SE specification of the neural plate border via canonical Wnt signaling is directed by Grhl3 as a downstream effector; Grhl3 acts downstream of canonical Wnt/DKK1/KREMEN1 signaling to specify surface ectoderm fate in the neural plate border, and this specification is crucial for neural tube closure. Comparative expression profiling between SE and NE lineages, canonical Wnt pathway manipulation, Grhl3 expression analysis in neural plate border EBioMedicine Medium 26288816
2017 GRHL3 binding and enhancer usage are dynamically rearranged as keratinocytes transition between states: GRHL3 binds preferentially to super-enhancers in differentiating keratinocytes, while during migration it binds preferentially to promoters along with REST to repress migration inhibitors. GRHL3 also represses formation of progenitor and non-keratinocyte super-enhancers in differentiating cells. ChIP-seq (GRHL3, H3K27ac), ATAC-seq, gene expression profiling in human keratinocytes (differentiated vs. migrating) PLoS genetics High 28445475
2017 BRD4 is required for maintenance of GRHL3 expression in non-transformed basal-like mammary epithelial cells; BRD4 occupancy at GRHL3 enhancers correlates with enhancer activity and eRNA transcription. Activation of FOXO1 function (via EGFR-AKT inhibition) promotes GRHL3 expression, while Src kinase activation and FOXO1 inhibition decrease it. BRD4 ChIP-seq, eRNA analysis, EGFR/AKT and Src inhibitor treatments, siRNA knockdown of BRD4 Nucleic acids research Medium 27980063
2018 During epidermal differentiation, GRHL3 undergoes cytoplasmic localization; this extranuclear GRHL3 is essential for membrane-associated expression of VANGL2 and CELSR1, thereby enabling epidermal cells to acquire mechanical properties for cell shape changes required for epithelial morphogenesis. GRHL3 acts downstream of Wnt/β-catenin in epidermal differentiation. Embryoid body differentiation in vitro, immunofluorescence (subcellular localization), VANGL2/CELSR1 expression analysis, Wnt signaling pathway analysis Nature communications Medium 30283008
2018 Loss of GRHL3 leads to upregulation of TARC/CCL17 (a chemokine) as a novel mediator of basal keratinocyte proliferation; GRHL3 knockdown in human keratinocytes identified TARC as the only significantly upregulated chemokine of 42 examined, and mouse skin lacking Grhl3 shows mast cell infiltration, T-cell infiltration, elevated CD3/pSTAT3, and basal keratinocyte hyperproliferation consistent with TARC-driven effects. GRHL3 siRNA knockdown (human keratinocytes), cytokine array, mouse Grhl3-KO skin analysis (immunohistochemistry, flow cytometry), 5-ASA rescue experiment Cell death & disease Medium 30341279
2019 The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation; overexpression of Irf6 causes exencephaly through suppression of Tfap2a and Grhl3 expression, and loss of Irf6 function reduces Tfap2a and Grhl3 expression in tail tissues, placing Irf6 upstream of Grhl3 in neural tube closure. Mouse genetics (Irf6 overexpression and loss-of-function), gene expression analysis (qRT-PCR, in situ hybridization), human spina bifida sequencing Human molecular genetics Medium 30689861
2020 GRHL3 is essential for suppressing epidermal stem cell expansion and suppresses Wnt signaling in stem cells; single-cell RNA-seq reveals that IFE differentiation is gradualistic with GRHL3 controlling transition from stem to transition cell states, in addition to activating terminal differentiation genes. Single-cell RNA-seq, RNA velocity analysis, GRHL3 conditional knockout mice, gene expression profiling Nature communications High 33116143
2021 GRHL3 activates FSCN1 (Fascin-1) transcription at the wound front, leading to decreased E-cadherin expression and relaxed adherens junctions between suprabasal keratinocytes, thereby promoting collective cell migration and wound closure; ATAC-seq on wounded keratinocytes shows decreased wound-induced chromatin accessibility near Fscn1 in Grhl3-cKO mice at a region enriched for GRHL3 motifs. Conditional knockout mice (Grhl3-cKO), ATAC-seq, wound healing assay, E-cadherin and FSCN1 expression analysis, ChIP/motif analysis JCI insight High 34494554
2021 Epidermal progenitors suppress full-length GRHL3 expression via CPSF-HNRNPA3-promoted intronic polyadenylation (IpA) at a site in the first intron of GRHL3; CRISPR knockout of the GRHL3 IpA site increased full-length GRHL3 mRNA. HNRNPA3 interacts with the CPSF complex to enhance site-specific IpA at GRHL3, preventing premature differentiation. CRISPR knockout of IpA site, CPSF knockdown, RNA-seq, protein interaction (CPSF-HNRNPA3 interaction), targeted genetic screen Nature communications High 33469008
2021 In zebrafish, Grhl3 induces retention of rounded epidermal cells by regulating E-cadherin levels; transcriptome and genetic interaction studies show that Grhl3 facilitates survival of myoVb-deficient embryos by regulating cell adhesion, cell retention, and epidermal architecture. Live imaging in zebrafish, transcriptome analysis, genetic interaction studies (grhl3 and myoVb), E-cadherin expression analysis PLoS genetics Medium 34570762
2022 GRHL3 is an initiation factor sufficient to drive surface epithelium (SE) commitment from human embryonic stem cells; GRHL3 primes SE chromatin accessibility landscape and activates SE-initiating gene expression. GRHL3-mediated promoter interactions reveal a positive feedback loop with BMP4 on SE fate decisions. hESC differentiation, Hi-C (cis-regulatory chromatin loop analysis), ATAC-seq, ChIP-seq, RNA-seq, GRHL3 overexpression Science advances High 35857527
2022 GRHL3 functions as a tumor suppressor in esophageal squamous cell carcinoma (ESCC) by regulating HOPX expression; HOPX limits Wnt/β-catenin signaling downstream of GRHL3. ChIP-seq and ChIP-PCR confirm GRHL3 directly regulates HOPX transcription, identifying a GRHL3/HOPX/Wnt/β-catenin proto-oncogenic axis. Conditional Grhl3 knockout mice, RNA-seq, ChIP-seq, ChIP-PCR, immunohistochemistry, patient samples Cellular and molecular gastroenterology and hepatology High 36442813
2024 GRHL3 directly activates APOBEC3A expression in terminally differentiating keratinocytes; single-cell RNA-seq and functional experiments show APOBEC3A expression is confined to terminally differentiating cells and requires GRHL3, whereas in squamous cell carcinoma GRHL3 activity expands to proliferating cells, extending APOBEC3A expression to replicating cells. Single-cell RNA-seq, immunohistochemistry, spatial transcriptomics, functional experiments in keratinocytes The EMBO journal Medium 39548236
2024 GRHL3 directly binds the lnc-DC promoter and upregulates lnc-DC expression during keratinocyte differentiation; lnc-DC in turn interacts with the RNA-binding protein IGF2BP2 to stabilize ZNF750 mRNA, upregulating downstream targets TINCR and KLF4, defining a GRHL3/lnc-DC/ZNF750 axis in epidermal differentiation. CUT&RUN assay (GRHL3 binding to lnc-DC promoter), RIP assay (lnc-DC/IGF2BP2 interaction), RNA stability assay, siRNA knockdown, overexpression, whole transcriptome sequencing Journal of dermatological science Medium 38383230
2024 GPX4, when overexpressed and enriched in the nucleus of HCC cells, transcriptionally silences GRHL3 expression, leading to PTEN downregulation and PI3K/AKT pathway activation promoting metastasis; GPX4 amino acids 110-145 constitute a binding site that interacts with the GRHL3 promoter. GPX4 overexpression in HCC cells, nuclear fractionation, ChIP/promoter binding assay, functional metastasis assays, FACS-based ROS analysis Translational research Medium 38797432

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis. Cancer cell 194 22094257
2013 Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. American journal of human genetics 189 24360809
2003 Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3. Nature medicine 159 14608380
2006 The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Developmental biology 152 16949565
2001 Analysis of codon usage diversity of bacterial genes with a self-organizing map (SOM): characterization of horizontally transferred genes with emphasis on the E. coli O157 genome. Gene 110 11591475
1986 Distribution and ontogeny of SP, CGRP, SOM, and VIP in chick sensory and sympathetic ganglia. Developmental biology 96 2426150
2014 Synaptic properties of SOM- and CCK-expressing cells in dentate gyrus interneuron networks. The Journal of neuroscience : the official journal of the Society for Neuroscience 94 24920624
2003 The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. The Biochemical journal 89 12549979
2012 GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program. PLoS genetics 84 22829784
2016 Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate. American journal of human genetics 83 27018475
2007 Weissellicin 110, a newly discovered bacteriocin from Weissella cibaria 110, isolated from plaa-som, a fermented fish product from Thailand. Applied and environmental microbiology 78 17293526
2009 The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation. The EMBO journal 68 19494835
2012 The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1. Oncogene 62 22614019
2012 Mining SOM expression portraits: feature selection and integrating concepts of molecular function. BioData mining 53 23043905
2008 Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure. Developmental biology 53 18485343
2014 A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia. The Journal of clinical investigation 52 25347468
2022 Quantitative source apportionment and associated driving factor identification for soil potential toxicity elements via combining receptor models, SOM, and geo-detector method. The Science of the total environment 47 35341851
2015 Fate Specification of Neural Plate Border by Canonical Wnt Signaling and Grhl3 is Crucial for Neural Tube Closure. EBioMedicine 47 26288816
2002 Fermentation and microflora of plaa-som, a thai fermented fish product prepared with different salt concentrations. International journal of food microbiology 47 11883675
2017 GRHL3 binding and enhancers rearrange as epidermal keratinocytes transition between functional states. PLoS genetics 46 28445475
2020 Murine interfollicular epidermal differentiation is gradualistic with GRHL3 controlling progression from stem to transition cell states. Nature communications 44 33116143
2008 Grhl3 and Lmo4 play coordinate roles in epidermal migration. Developmental biology 43 18619436
2007 Modeling robust QSAR 3: SOM-4D-QSAR with iterative variable elimination IVE-PLS: application to steroid, azo dye, and benzoic acid series. Journal of chemical information and modeling 39 17567123
2005 The epidermis of grhl3-null mice displays altered lipid processing and cellular hyperproliferation. Organogenesis 38 19521564
2020 Porphyromonas gingivalis Promotes the Proliferation and Migration of Esophageal Squamous Cell Carcinoma through the miR-194/GRHL3/PTEN/Akt Axis. ACS infectious diseases 36 32298082
2017 Rare deleterious variants in GRHL3 are associated with human spina bifida. Human mutation 33 28276201
2016 Distinct Roles of SOM and VIP Interneurons during Cortical Up States. Frontiers in neural circuits 33 27507936
2019 The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation. Human molecular genetics 31 30689861
2022 PathDetect-SOM: A Neural Network Approach for the Identification of Pathways in Ligand Binding Simulations. Journal of chemical theory and computation 30 35213804
2017 Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate. Journal of dental research 29 28886269
2018 Loss of GRHL3 leads to TARC/CCL17-mediated keratinocyte proliferation in the epidermis. Cell death & disease 28 30341279
1996 SOM 1, a small new gene required for mitochondrial inner membrane peptidase function in Saccharomyces cerevisiae. Molecular & general genetics : MGG 28 8879245
2017 BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells. Nucleic acids research 27 27980063
2010 Identification of lactic acid bacteria associated with the production of plaa-som, a traditional fermented fish product of Thailand. International journal of food microbiology 26 20167386
2021 Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration. Nature communications 25 33469008
2016 Grhl3 modulates epithelial structure formation of the circumvallate papilla during mouse development. Histochemistry and cell biology 25 27586853
2005 Recognizing partially occluded, expression variant faces from single training image per person with SOM and soft kappa-NN ensemble. IEEE transactions on neural networks 25 16121729
2021 GRHL3 activates FSCN1 to relax cell-cell adhesions between migrating keratinocytes during wound reepithelialization. JCI insight 23 34494554
2016 Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin. Acta biochimica et biophysica Sinica 23 26837418
2012 Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors. Endocrine-related cancer 23 22736724
2020 Effect of soil organic matter (SOM) on the degradation of polycyclic aromatic hydrocarbons using Pleurotus dryinus IBB 903-A microcosm study. Journal of environmental management 22 32090843
2024 GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis. Translational research : the journal of laboratory and clinical medicine 21 38797432
2018 Cytoplasmic localization of GRHL3 upon epidermal differentiation triggers cell shape change for epithelial morphogenesis. Nature communications 21 30283008
2015 Upregulation of miR21 and repression of Grhl3 by leptin mediates sinusoidal endothelial injury in experimental nonalcoholic steatohepatitis. PloS one 20 25658689
2015 Intrahepatic cholestasis of pregnancy with concomitant hepatitis C virus infection, Joan C. Edwards SOM, Marshall University. European journal of gastroenterology & hepatology 19 25874507
2011 The transcription factor Grainyhead like 3 (GRHL3) affects endothelial cell apoptosis and migration in a NO-dependent manner. Biochemical and biophysical research communications 19 21856281
2010 Changes in the somatostatin (SOM)-like immunoreactivity within nervous structures of the porcine descending colon under various pathological factors. Experimental and molecular pathology 19 20138863
2010 Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation. Birth defects research. Part A, Clinical and molecular teratology 19 20589880
2020 Structure-Based Site of Metabolism (SOM) Prediction of Ligand for CYP3A4 Enzyme: Comparison of Glide XP and Induced Fit Docking (IFD). Molecules (Basel, Switzerland) 17 32244772
2018 Hypomethylation of GRHL3 gene is associated with the occurrence of neural tube defects. Epigenomics 17 29587534
2018 Carbon monoxide signal regulates light-initiated seed germination by suppressing SOM expression. Plant science : an international journal of experimental plant biology 17 29807609
2018 Arsenic biosorption using pretreated biomass of psychrotolerant Yersinia sp. strain SOM-12D3 isolated from Svalbard, Arctic. Environmental science and pollution research international 17 30062542
2016 Association study between Van der Woude Syndrome causative gene GRHL3 and nonsyndromic cleft lip with or without cleft palate in a Chinese cohort. Gene 17 27129939
2016 Lactobacillus futsaii CS3, a New GABA-Producing Strain Isolated from Thai Fermented Shrimp (Kung-Som). Indian journal of microbiology 17 28611499
1988 Psychopharmacological consequences of activation of beta adrenergic receptors by SOM-1122. The Journal of pharmacology and experimental therapeutics 16 2899168
2017 Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice. Developmental neurobiology 15 27907249
2017 Inhibition of Staphylococcus aureus in vitro by bacteriocinogenic Lactococcus lactis KTH0-1S isolated from Thai fermented shrimp (Kung-som) and safety evaluation. Archives of microbiology 15 28058488
2022 Cis-regulatory chromatin loops analysis identifies GRHL3 as a master regulator of surface epithelium commitment. Science advances 14 35857527
2021 Comprehensive characterization of oscillatory signatures in a model circuit with PV- and SOM-expressing interneurons. Biological cybernetics 14 34628539
2002 Genotypic and phenotypic characterization of garlic-fermenting lactic acid bacteria isolated from som-fak, a Thai low-salt fermented fish product. Journal of applied microbiology 14 11849359
2014 Biodegradation of pyrene by Phanerochaete chrysosporium and enzyme activities in soils: effect of SOM, sterilization and aging. Journal of environmental sciences (China) 13 25079644
2012 Classification of Aurora kinase inhibitors by self-organizing map (SOM) and support vector machine (SVM). European journal of medicinal chemistry 12 22796044
2008 Hyperbolic SOM-based clustering of DNA fragment features for taxonomic visualization and classification. Bioinformatics (Oxford, England) 12 18535082
2021 The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity. Molecular therapy : the journal of the American Society of Gene Therapy 11 33775911
2017 Knockdown of GRHL3 inhibits activities and induces cell cycle arrest and apoptosis of human colorectal cancer cells. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 11 29270747
2016 MiRNATIP: a SOM-based miRNA-target interactions predictor. BMC bioinformatics 11 28185545
2010 Grhl3 and GEF19 in the front rho. Small GTPases 11 21686262
2005 Histological heterogeneity of human glioblastomas investigated with an unsupervised neural network (SOM). Histology and histopathology 11 15736037
2022 A striatal SOM-driven ChAT-iMSN loop generates beta oscillations and produces motor deficits. Cell reports 10 35858550
2021 GRHL3 Promotes Tumor Growth and Metastasis via the MEK Pathway in Colorectal Cancer. Analytical cellular pathology (Amsterdam) 10 34888136
2016 Lack of Association between Missense Variants in GRHL3 (rs2486668 and rs545809) and Susceptibility to Non-Syndromic Orofacial Clefts in a Han Chinese Population. PloS one 10 27459192
2022 Distribution of Kazachstania Yeast in Thai Traditional Fermented Fish (Plaa-Som) in Northeastern Thailand. Journal of fungi (Basel, Switzerland) 9 36294595
2022 Identification of a Novel GRHL3/HOPX/Wnt/β-Catenin Proto-oncogenic Axis in Squamous Cell Carcinoma of the Esophagus. Cellular and molecular gastroenterology and hepatology 9 36442813
2025 ProFun-SOM: Protein Function Prediction for Specific Ontology Based on Multiple Sequence Alignment Reconstruction. IEEE transactions on neural networks and learning systems 8 38980781
2022 Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas. Frontiers in oncology 8 36457487
2019 Novel computational model of gastrula morphogenesis to identify spatial discriminator genes by self-organizing map (SOM) clustering. Scientific reports 8 31467377
2016 Self-Organizing Map (SOM) and Support Vector Machine (SVM) Models for the Prediction of Human Epidermal Growth Factor Receptor (EGFR/ ErbB-1) Inhibitors. Combinatorial chemistry & high throughput screening 8 27074760
2015 Differences in SOM decomposition and temperature sensitivity among soil aggregate size classes in a temperate grasslands. PloS one 8 25692291
2014 Structure-based modeling of dye-fiber affinity with SOM-4D-QSAR paradigm: application to set of anthraquinone derivatives. Combinatorial chemistry & high throughput screening 8 24499310
2003 A SOM projection technique with the growing structure for visualizing high-dimensional data. International journal of neural systems 8 14652875
2024 Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma. The EMBO journal 7 39548236
2022 Transcriptional states of CAR-T infusion relate to neurotoxicity - lessons from high-resolution single-cell SOM expression portraying. Frontiers in immunology 7 36248848
2020 Expression Analysis of GRHL3 and PHLDA3 in Head and Neck Squamous Cell Carcinoma. Cancer management and research 7 32581582
2013 In silico prediction of cytochrome P450-mediated site of metabolism (SOM). Protein and peptide letters 7 22591483
2023 Water-soluble organic carbon (WSOC) from vegetation fire and its differences from WSOC in natural media: Spectral comparison and self-organizing maps (SOM) classification. The Science of the total environment 6 37385508
2019 Genetic variants in GRHL3 and risk for neural tube defects: A case-control and case-parent triad/control study. Birth defects research 6 31332962
2023 Genome sequences and functional analysis of Levilactobacillus brevis LSF9-1 and Pediococcus acidilactici LSF1-1 from fermented fish cake (Som-fak) with gamma-aminobutyric acid (GABA) production. Functional & integrative genomics 5 37171680
2021 Grhl3 promotes retention of epidermal cells under endocytic stress to maintain epidermal architecture in zebrafish. PLoS genetics 5 34570762
2016 Clinical significance of GRHL3 expression in diffuse large B cell lymphoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 5 26797800
2014 Distribution of peptidergic populations in the human dentate gyrus (somatostatin [SOM-28, SOM-12] and neuropeptide Y [NPY]) during postnatal development. Cell and tissue research 5 24965867
2011 Classification of Aurora-A Kinase Inhibitors Using Self-Organizing Map (SOM) and Support Vector Machine (SVM). Molecular informatics 5 27467876
2025 QTL Mapping and Developing KASP Markers for High-Temperature Adult-Plant Resistance to Stripe Rust in Argentinian Spring Wheat William Som (PI 184597). International journal of molecular sciences 4 40507883
2020 ShinySOM: graphical SOM-based analysis of single-cell cytometry data. Bioinformatics (Oxford, England) 4 32049322
2005 Prediction Models for DNA Transcription Termination Based on SOM Networks. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference 4 17281313
1996 [Expression of somatostatin mRNA and coexistence of SOM mRNA and 5-HT in nucleus raphe dorsalis following noxious stimulation and electroacupuncture analgesia]. Zhen ci yan jiu = Acupuncture research 4 9387336
2021 Association of Nucleotide Variants of GRHL3, IRF6, NAT2, SDC2, BCL3, and PVRL1 Genes with Nonsyndromic Cleft Lip With/Without Cleft Palate in Multigenerational Families: A Retrospective Study. Contemporary clinical dentistry 3 34220153
2021 Association analysis of SNPs in GRHL3, FAF1, and KCNJ2 with NSCPO sub-phenotypes in Han Chinese. Oral diseases 3 34255421
2010 Phylogenetic diversity of gene sequences isolated from the rumen as analysed using a self-organizing map (SOM). Journal of applied microbiology 3 20233261
2024 The GRHL3-regulated long non-coding RNA lnc-DC modulates keratinocytes differentiation by interacting with IGF2BP2 and up-regulating ZNF750. Journal of dermatological science 2 38383230
2009 Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster. Clinical & experimental metastasis 2 19521786

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