{"gene":"GRHL3","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2003,"finding":"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.","method":"Protein interaction studies (pulldown/co-IP), phylogenetic and domain analysis, alternative splicing characterization","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — protein interaction pulldown from single lab, supported by domain analysis across multiple isoforms","pmids":["12549979"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Gene targeting (knockout mice), genetic complementation, mapping studies","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic complementation, knockout phenotype, and mapping in a single rigorous study with multiple orthogonal genetic approaches","pmids":["14608380"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Gene knockout (null mice), gene expression analysis, ultrastructural analysis","journal":"Organogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype with defined molecular target, single lab","pmids":["19521564"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Protein interaction (co-IP), genetic interaction (double knockout mice), barrier function assays, histology","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic interaction confirmed by double KO, co-expression and protein interaction in same study","pmids":["16949565"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Knockout mice (eye-open phenotype), organ culture, immunofluorescence, western blot (phospho-EGFR, phospho-ERK), TGFα rescue experiment","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO phenotype with defined pathway placement, ligand rescue experiment, multiple orthogonal methods","pmids":["18485343"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Biochemical interaction (co-IP), double knockout mouse genetics, in vitro scratch assay, immunofluorescence, western blot","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction plus double-KO genetic confirmation, multiple phenotypic readouts","pmids":["18619436"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Knockout mice, genome-wide expression profiling, ChIP (direct promoter binding), reporter assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP evidence for target gene, KO phenotype, multiple orthogonal methods in single study","pmids":["19494835"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Conditional knockout mice, ChIP (PTEN as direct target), Pten rescue experiment, tumor assays","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct target identified by ChIP, genetic rescue fully abrogates phenotype, conditional KO","pmids":["22094257"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA knockdown in endothelial cells, migration assay, apoptosis assay, western blot (phospho-Akt, phospho-eNOS)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, siRNA KD with defined molecular readouts, multiple phenotypic assays","pmids":["21856281"],"is_preprint":false},{"year":2012,"finding":"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.","method":"miRNA profiling, ChIP (miR-21 promoter binding by GRHL3), luciferase reporter assay, overexpression/knockdown in keratinocytes, tumor xenograft assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding by ChIP plus functional rescue, multiple orthogonal methods","pmids":["22614019"],"is_preprint":false},{"year":2012,"finding":"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.","method":"ChIP-seq, gene expression profiling, genome-wide analysis in epidermis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq genome-wide evidence for Trithorax recruitment, single lab","pmids":["22829784"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Sequencing of VWS families, zebrafish functional assay, mouse knockout/double heterozygote genetic epistasis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional zebrafish assay, mouse genetics with epistasis analysis, multiple orthogonal approaches","pmids":["24360809"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Conditional knockout mice, imiquimod model, ChIP-Seq, gene expression profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP-Seq, expression profiling, pharmacological rescue, multiple orthogonal methods","pmids":["25347468"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Rodent NASH models, transgenic mice (leptin/leptin receptor null), western blot, qRT-PCR, immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple mouse models with consistent results, mechanistic link through miR-21/Grhl3/NOS3 axis, single lab","pmids":["25658689"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Comparative expression profiling between SE and NE lineages, canonical Wnt pathway manipulation, Grhl3 expression analysis in neural plate border","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression profiling combined with pathway analysis, single lab, mechanistic placement downstream of Wnt","pmids":["26288816"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP-seq (GRHL3, H3K27ac), ATAC-seq, gene expression profiling in human keratinocytes (differentiated vs. migrating)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq and chromatin profiling with multiple orthogonal methods, functional implications in two cell states","pmids":["28445475"],"is_preprint":false},{"year":2017,"finding":"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.","method":"BRD4 ChIP-seq, eRNA analysis, EGFR/AKT and Src inhibitor treatments, siRNA knockdown of BRD4","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with functional pathway inhibitor experiments, single lab","pmids":["27980063"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Embryoid body differentiation in vitro, immunofluorescence (subcellular localization), VANGL2/CELSR1 expression analysis, Wnt signaling pathway analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by imaging with functional consequence, mechanistic link to PCP components, single lab","pmids":["30283008"],"is_preprint":false},{"year":2018,"finding":"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.","method":"GRHL3 siRNA knockdown (human keratinocytes), cytokine array, mouse Grhl3-KO skin analysis (immunohistochemistry, flow cytometry), 5-ASA rescue experiment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cytokine array plus KO mouse confirmation, single lab, two experimental systems","pmids":["30341279"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Mouse genetics (Irf6 overexpression and loss-of-function), gene expression analysis (qRT-PCR, in situ hybridization), human spina bifida sequencing","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with gain- and loss-of-function, single lab","pmids":["30689861"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Single-cell RNA-seq, RNA velocity analysis, GRHL3 conditional knockout mice, gene expression profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — scRNA-seq with RNA velocity plus conditional KO, multiple orthogonal methods, identifies Wnt suppression mechanism","pmids":["33116143"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Conditional knockout mice (Grhl3-cKO), ATAC-seq, wound healing assay, E-cadherin and FSCN1 expression analysis, ChIP/motif analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — ATAC-seq chromatin accessibility, conditional KO, defined GRHL3/FSCN1/E-cadherin pathway, multiple orthogonal methods","pmids":["34494554"],"is_preprint":false},{"year":2021,"finding":"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.","method":"CRISPR knockout of IpA site, CPSF knockdown, RNA-seq, protein interaction (CPSF-HNRNPA3 interaction), targeted genetic screen","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR-based functional validation, protein interaction, RNA-seq, multiple orthogonal methods in single study","pmids":["33469008"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Live imaging in zebrafish, transcriptome analysis, genetic interaction studies (grhl3 and myoVb), E-cadherin expression analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with functional consequence, genetic interaction, transcriptome, single lab","pmids":["34570762"],"is_preprint":false},{"year":2022,"finding":"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.","method":"hESC differentiation, Hi-C (cis-regulatory chromatin loop analysis), ATAC-seq, ChIP-seq, RNA-seq, GRHL3 overexpression","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genome-wide chromatin methods plus functional overexpression, positive feedback loop validated","pmids":["35857527"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Conditional Grhl3 knockout mice, RNA-seq, ChIP-seq, ChIP-PCR, immunohistochemistry, patient samples","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse, ChIP-seq/ChIP-PCR direct target evidence, RNA-seq, patient validation","pmids":["36442813"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Single-cell RNA-seq, immunohistochemistry, spatial transcriptomics, functional experiments in keratinocytes","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq with functional validation, single lab, consistent with differentiation-state model","pmids":["39548236"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&RUN for direct binding, RIP for RNA-protein interaction, multiple orthogonal methods, single lab","pmids":["38383230"],"is_preprint":false},{"year":2024,"finding":"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.","method":"GPX4 overexpression in HCC cells, nuclear fractionation, ChIP/promoter binding assay, functional metastasis assays, FACS-based ROS analysis","journal":"Translational research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter binding domain identified, functional assays, single lab","pmids":["38797432"],"is_preprint":false}],"current_model":"GRHL3 is an epithelial transcription factor that acts as a master regulator of surface epithelium commitment, epidermal differentiation, and barrier integrity by directly binding and activating differentiation gene targets (including PTEN, TGase 1, uroplakin II, FSCN1, HOPX, APOBEC3A) and repressing proliferative/stem cell programs (including miR-21, Wnt signaling); it dimerizes with other GRHL family members and functionally cooperates with LMO4 to regulate neural tube closure, eyelid closure, and wound repair through the EGFR/ERK and Rho GTPase/actin pathways, while its expression is post-transcriptionally suppressed in progenitors via CPSF-HNRNPA3-mediated intronic polyadenylation and transcriptionally regulated upstream by the TFAP2A-IRF6-Wnt signaling axis."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2003,"claim":"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","pmids":["12549979"],"confidence":"Medium","gaps":["No direct DNA target or functional consequence of dimerization shown","Dimerization assayed in vitro without in vivo confirmation"]},{"year":2003,"claim":"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","pmids":["14608380"],"confidence":"High","gaps":["Direct transcriptional targets in neural tube not identified here","Mechanism of closure failure unresolved at the molecular level"]},{"year":2005,"claim":"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","pmids":["19521564"],"confidence":"Medium","gaps":["Direct promoter binding to TGase1 not demonstrated in this study","Single lab"]},{"year":2006,"claim":"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","pmids":["16949565"],"confidence":"High","gaps":["Structural basis of GRHL3-LMO4 interaction unknown","Whether LMO4 alters target-gene selection not defined"]},{"year":2008,"claim":"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","pmids":["18485343","18619436"],"confidence":"High","gaps":["Direct transcriptional target driving TGFα/ERK not pinpointed","Cytoskeletal effectors downstream not fully mapped"]},{"year":2009,"claim":"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","pmids":["19494835"],"confidence":"High","gaps":["Histone-modification context of selective binding only partially defined","Cofactor requirements at the uroplakin promoter unclear"]},{"year":2011,"claim":"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","pmids":["22094257"],"confidence":"High","gaps":["Whether other GRHL3 targets contribute to SCC suppression not resolved here"]},{"year":2011,"claim":"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","pmids":["21856281"],"confidence":"Medium","gaps":["Direct transcriptional targets in endothelium not identified","siRNA only, single lab"]},{"year":2012,"claim":"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","pmids":["22614019","22829784"],"confidence":"High","gaps":["Mechanism of Trithorax complex recruitment to GRHL3 sites not defined","How GRHL3 switches between activation and repression unresolved"]},{"year":2013,"claim":"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","pmids":["24360809"],"confidence":"High","gaps":["Periderm target genes of GRHL3 not identified","Penetrance determinants of cleft palate unexplained"]},{"year":2014,"claim":"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","pmids":["25347468"],"confidence":"High","gaps":["Determinants of context-specific binding not defined","Cofactors distinguishing development vs repair targets unknown"]},{"year":2015,"claim":"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","pmids":["26288816","25658689"],"confidence":"Medium","gaps":["Direct Wnt-responsive elements controlling Grhl3 not mapped","Causal vs correlative role in NASH endothelium not fully separated"]},{"year":2017,"claim":"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","pmids":["28445475","27980063"],"confidence":"High","gaps":["Mechanism redirecting GRHL3 to super-enhancers vs promoters unknown","Functional cooperation with REST during migration only partially defined"]},{"year":2018,"claim":"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","pmids":["30283008","30341279"],"confidence":"Medium","gaps":["Mechanism of GRHL3 cytoplasmic relocalization unknown","Whether TARC regulation is direct not established"]},{"year":2019,"claim":"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","pmids":["30689861"],"confidence":"Medium","gaps":["Direct regulatory connections among TFAP2A, IRF6, and GRHL3 not shown","Single lab"]},{"year":2020,"claim":"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","pmids":["33116143"],"confidence":"High","gaps":["Direct Wnt-pathway targets in stem cells not identified","Switch-controlling cofactors undefined"]},{"year":2021,"claim":"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","pmids":["34494554","34570762","33469008"],"confidence":"High","gaps":["How HNRNPA3 directs CPSF specifically to the GRHL3 intron not fully resolved","Signals triggering the IpA switch during differentiation unknown"]},{"year":2022,"claim":"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","pmids":["35857527","36442813"],"confidence":"High","gaps":["Pioneer-factor mechanism of chromatin priming not mechanistically dissected","How GRHL3 activity is restrained in carcinoma cells unclear"]},{"year":2024,"claim":"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","pmids":["39548236","38383230","38797432"],"confidence":"Medium","gaps":["Consequence of expanded APOBEC3A expression to proliferating SCC cells not fully tested","Mechanism by which nuclear GPX4 silences the GRHL3 promoter incompletely defined"]},{"year":null,"claim":"How GRHL3 selects context-specific target sets and switches between gene activation and repression across cell states remains the central unresolved mechanistic question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,6,7,9,25,26,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[6,7,9,25,27]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,7,15,24]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,11,14,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,9,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,11,25,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,14,20]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10,15,24]}],"complexes":[],"partners":["GRHL1","GRHL2","LMO4","REST"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TE85","full_name":"Grainyhead-like protein 3 homolog","aliases":["Sister of mammalian grainyhead","Transcription factor CP2-like 4"],"length_aa":626,"mass_kda":70.3,"function":"Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin (By similarity). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (PubMed:21081122, PubMed:25347468). xhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair (By similarity). Exhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair but is essential to form the epidermal barrier with TGM3 as critical direct target gene among others. Despite being dispensable during normal epidermal homeostasis in the adulthood, is again required for barrier repair after immune-mediated epidermal damage, regulates distinct gene batteries in embryonic epidermal differentiation and adult epidermal barrier reformation after injury. Plays unique and cooperative roles with GRHL2 in establishing distinct zones of primary neurulation. Essential for spinal closure, functions cooperatively with GRHL2 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Also required for proper development of the oral periderm (PubMed:24360809). No genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity (PubMed:21081122)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q8TE85/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GRHL3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRHL3","total_profiled":1310},"omim":[{"mim_id":"610226","title":"ZINC FINGER PROTEIN 750; ZNF750","url":"https://www.omim.org/entry/610226"},{"mim_id":"609786","title":"GRAINYHEAD-LIKE 1; GRHL1","url":"https://www.omim.org/entry/609786"},{"mim_id":"608576","title":"GRAINYHEAD-LIKE 2; GRHL2","url":"https://www.omim.org/entry/608576"},{"mim_id":"608317","title":"GRAINYHEAD-LIKE 3; GRHL3","url":"https://www.omim.org/entry/608317"},{"mim_id":"606713","title":"VAN DER WOUDE SYNDROME 2; VWS2","url":"https://www.omim.org/entry/606713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":102.2},{"tissue":"skin 1","ntpm":49.4},{"tissue":"vagina","ntpm":42.5}],"url":"https://www.proteinatlas.org/search/GRHL3"},"hgnc":{"alias_symbol":["SOM"],"prev_symbol":["TFCP2L4"]},"alphafold":{"accession":"Q8TE85","domains":[{"cath_id":"2.60.40","chopping":"233-417_442-450","consensus_level":"high","plddt":90.0972,"start":233,"end":450},{"cath_id":"3.10.20","chopping":"511-624","consensus_level":"high","plddt":58.5476,"start":511,"end":624}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TE85","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TE85-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TE85-F1-predicted_aligned_error_v6.png","plddt_mean":60.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRHL3","jax_strain_url":"https://www.jax.org/strain/search?query=GRHL3"},"sequence":{"accession":"Q8TE85","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TE85.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TE85/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TE85"}},"corpus_meta":[{"pmid":"22094257","id":"PMC_22094257","title":"Targeting of the tumor suppressor GRHL3 by a miR-21-dependent proto-oncogenic network results in PTEN loss and tumorigenesis.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/22094257","citation_count":194,"is_preprint":false},{"pmid":"24360809","id":"PMC_24360809","title":"Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24360809","citation_count":189,"is_preprint":false},{"pmid":"14608380","id":"PMC_14608380","title":"Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3.","date":"2003","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/14608380","citation_count":159,"is_preprint":false},{"pmid":"16949565","id":"PMC_16949565","title":"The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16949565","citation_count":152,"is_preprint":false},{"pmid":"11591475","id":"PMC_11591475","title":"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.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11591475","citation_count":110,"is_preprint":false},{"pmid":"2426150","id":"PMC_2426150","title":"Distribution and ontogeny of SP, CGRP, SOM, and VIP in chick sensory and sympathetic ganglia.","date":"1986","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/2426150","citation_count":96,"is_preprint":false},{"pmid":"24920624","id":"PMC_24920624","title":"Synaptic properties of SOM- and CCK-expressing cells in dentate gyrus interneuron networks.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24920624","citation_count":94,"is_preprint":false},{"pmid":"12549979","id":"PMC_12549979","title":"The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12549979","citation_count":89,"is_preprint":false},{"pmid":"22829784","id":"PMC_22829784","title":"GRHL3/GET1 and trithorax group members collaborate to activate the epidermal progenitor differentiation program.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22829784","citation_count":84,"is_preprint":false},{"pmid":"27018475","id":"PMC_27018475","title":"Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27018475","citation_count":83,"is_preprint":false},{"pmid":"17293526","id":"PMC_17293526","title":"Weissellicin 110, a newly discovered bacteriocin from Weissella cibaria 110, isolated from plaa-som, a fermented fish product from Thailand.","date":"2007","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17293526","citation_count":78,"is_preprint":false},{"pmid":"19494835","id":"PMC_19494835","title":"The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19494835","citation_count":68,"is_preprint":false},{"pmid":"22614019","id":"PMC_22614019","title":"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.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22614019","citation_count":62,"is_preprint":false},{"pmid":"23043905","id":"PMC_23043905","title":"Mining SOM expression portraits: feature selection and integrating concepts of molecular function.","date":"2012","source":"BioData mining","url":"https://pubmed.ncbi.nlm.nih.gov/23043905","citation_count":53,"is_preprint":false},{"pmid":"18485343","id":"PMC_18485343","title":"Grainyhead-like factor Get1/Grhl3 regulates formation of the epidermal leading edge during eyelid closure.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18485343","citation_count":53,"is_preprint":false},{"pmid":"25347468","id":"PMC_25347468","title":"A GRHL3-regulated repair pathway suppresses immune-mediated epidermal hyperplasia.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/25347468","citation_count":52,"is_preprint":false},{"pmid":"26288816","id":"PMC_26288816","title":"Fate Specification of Neural Plate Border by Canonical Wnt Signaling and Grhl3 is Crucial for Neural Tube Closure.","date":"2015","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/26288816","citation_count":47,"is_preprint":false},{"pmid":"35341851","id":"PMC_35341851","title":"Quantitative source apportionment and associated driving factor identification for soil potential toxicity elements via combining receptor models, SOM, and geo-detector method.","date":"2022","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/35341851","citation_count":47,"is_preprint":false},{"pmid":"11883675","id":"PMC_11883675","title":"Fermentation and microflora of plaa-som, a thai fermented fish product prepared with different salt concentrations.","date":"2002","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11883675","citation_count":47,"is_preprint":false},{"pmid":"28445475","id":"PMC_28445475","title":"GRHL3 binding and enhancers rearrange as epidermal keratinocytes transition between functional states.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28445475","citation_count":46,"is_preprint":false},{"pmid":"33116143","id":"PMC_33116143","title":"Murine interfollicular epidermal differentiation is gradualistic with GRHL3 controlling progression from stem to transition cell states.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33116143","citation_count":44,"is_preprint":false},{"pmid":"18619436","id":"PMC_18619436","title":"Grhl3 and Lmo4 play coordinate roles in epidermal migration.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18619436","citation_count":43,"is_preprint":false},{"pmid":"17567123","id":"PMC_17567123","title":"Modeling robust QSAR 3: SOM-4D-QSAR with iterative variable elimination IVE-PLS: application to steroid, azo dye, and benzoic acid series.","date":"2007","source":"Journal of chemical information and modeling","url":"https://pubmed.ncbi.nlm.nih.gov/17567123","citation_count":39,"is_preprint":false},{"pmid":"19521564","id":"PMC_19521564","title":"The epidermis of grhl3-null mice displays altered lipid processing and cellular hyperproliferation.","date":"2005","source":"Organogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/19521564","citation_count":38,"is_preprint":false},{"pmid":"32298082","id":"PMC_32298082","title":"Porphyromonas gingivalis Promotes the Proliferation and Migration of Esophageal Squamous Cell Carcinoma through the miR-194/GRHL3/PTEN/Akt Axis.","date":"2020","source":"ACS infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32298082","citation_count":36,"is_preprint":false},{"pmid":"28276201","id":"PMC_28276201","title":"Rare deleterious variants in GRHL3 are associated with human spina bifida.","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28276201","citation_count":33,"is_preprint":false},{"pmid":"27507936","id":"PMC_27507936","title":"Distinct Roles of SOM and VIP Interneurons during Cortical Up States.","date":"2016","source":"Frontiers in neural circuits","url":"https://pubmed.ncbi.nlm.nih.gov/27507936","citation_count":33,"is_preprint":false},{"pmid":"30689861","id":"PMC_30689861","title":"The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30689861","citation_count":31,"is_preprint":false},{"pmid":"35213804","id":"PMC_35213804","title":"PathDetect-SOM: A Neural Network Approach for the Identification of Pathways in Ligand Binding Simulations.","date":"2022","source":"Journal of chemical theory and computation","url":"https://pubmed.ncbi.nlm.nih.gov/35213804","citation_count":30,"is_preprint":false},{"pmid":"28886269","id":"PMC_28886269","title":"Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate.","date":"2017","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/28886269","citation_count":29,"is_preprint":false},{"pmid":"30341279","id":"PMC_30341279","title":"Loss of GRHL3 leads to TARC/CCL17-mediated keratinocyte proliferation in the epidermis.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30341279","citation_count":28,"is_preprint":false},{"pmid":"8879245","id":"PMC_8879245","title":"SOM 1, a small new gene required for mitochondrial inner membrane peptidase function in Saccharomyces cerevisiae.","date":"1996","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/8879245","citation_count":28,"is_preprint":false},{"pmid":"27980063","id":"PMC_27980063","title":"BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/27980063","citation_count":27,"is_preprint":false},{"pmid":"20167386","id":"PMC_20167386","title":"Identification of lactic acid bacteria associated with the production of plaa-som, a traditional fermented fish product of Thailand.","date":"2010","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20167386","citation_count":26,"is_preprint":false},{"pmid":"33469008","id":"PMC_33469008","title":"Epidermal progenitors suppress GRHL3-mediated differentiation through intronic polyadenylation promoted by CPSF-HNRNPA3 collaboration.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33469008","citation_count":25,"is_preprint":false},{"pmid":"27586853","id":"PMC_27586853","title":"Grhl3 modulates epithelial structure formation of the circumvallate papilla during mouse development.","date":"2016","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/27586853","citation_count":25,"is_preprint":false},{"pmid":"16121729","id":"PMC_16121729","title":"Recognizing partially occluded, expression variant faces from single training image per person with SOM and soft kappa-NN ensemble.","date":"2005","source":"IEEE transactions on neural networks","url":"https://pubmed.ncbi.nlm.nih.gov/16121729","citation_count":25,"is_preprint":false},{"pmid":"34494554","id":"PMC_34494554","title":"GRHL3 activates FSCN1 to relax cell-cell adhesions between migrating keratinocytes during wound reepithelialization.","date":"2021","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/34494554","citation_count":23,"is_preprint":false},{"pmid":"26837418","id":"PMC_26837418","title":"Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin.","date":"2016","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/26837418","citation_count":23,"is_preprint":false},{"pmid":"22736724","id":"PMC_22736724","title":"Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors.","date":"2012","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/22736724","citation_count":23,"is_preprint":false},{"pmid":"32090843","id":"PMC_32090843","title":"Effect of soil organic matter (SOM) on the degradation of polycyclic aromatic hydrocarbons using Pleurotus dryinus IBB 903-A microcosm study.","date":"2020","source":"Journal of environmental management","url":"https://pubmed.ncbi.nlm.nih.gov/32090843","citation_count":22,"is_preprint":false},{"pmid":"38797432","id":"PMC_38797432","title":"GPX4 transcriptionally promotes liver cancer metastasis via GRHL3/PTEN/PI3K/AKT axis.","date":"2024","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38797432","citation_count":21,"is_preprint":false},{"pmid":"30283008","id":"PMC_30283008","title":"Cytoplasmic localization of GRHL3 upon epidermal differentiation triggers cell shape change for epithelial morphogenesis.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30283008","citation_count":21,"is_preprint":false},{"pmid":"25658689","id":"PMC_25658689","title":"Upregulation of miR21 and repression of Grhl3 by leptin mediates sinusoidal endothelial injury in experimental nonalcoholic steatohepatitis.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25658689","citation_count":20,"is_preprint":false},{"pmid":"21856281","id":"PMC_21856281","title":"The transcription factor Grainyhead like 3 (GRHL3) affects endothelial cell apoptosis and migration in a NO-dependent manner.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21856281","citation_count":19,"is_preprint":false},{"pmid":"20589880","id":"PMC_20589880","title":"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.","date":"2010","source":"Birth defects research. Part A, Clinical and molecular teratology","url":"https://pubmed.ncbi.nlm.nih.gov/20589880","citation_count":19,"is_preprint":false},{"pmid":"20138863","id":"PMC_20138863","title":"Changes in the somatostatin (SOM)-like immunoreactivity within nervous structures of the porcine descending colon under various pathological factors.","date":"2010","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20138863","citation_count":19,"is_preprint":false},{"pmid":"25874507","id":"PMC_25874507","title":"Intrahepatic cholestasis of pregnancy with concomitant hepatitis C virus infection, Joan C. Edwards SOM, Marshall University.","date":"2015","source":"European journal of gastroenterology & hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/25874507","citation_count":19,"is_preprint":false},{"pmid":"29587534","id":"PMC_29587534","title":"Hypomethylation of GRHL3 gene is associated with the occurrence of neural tube defects.","date":"2018","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/29587534","citation_count":17,"is_preprint":false},{"pmid":"27129939","id":"PMC_27129939","title":"Association study between Van der Woude Syndrome causative gene GRHL3 and nonsyndromic cleft lip with or without cleft palate in a Chinese cohort.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27129939","citation_count":17,"is_preprint":false},{"pmid":"29807609","id":"PMC_29807609","title":"Carbon monoxide signal regulates light-initiated seed germination by suppressing SOM expression.","date":"2018","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/29807609","citation_count":17,"is_preprint":false},{"pmid":"32244772","id":"PMC_32244772","title":"Structure-Based Site of Metabolism (SOM) Prediction of Ligand for CYP3A4 Enzyme: Comparison of Glide XP and Induced Fit Docking (IFD).","date":"2020","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32244772","citation_count":17,"is_preprint":false},{"pmid":"30062542","id":"PMC_30062542","title":"Arsenic biosorption using pretreated biomass of psychrotolerant Yersinia sp. strain SOM-12D3 isolated from Svalbard, Arctic.","date":"2018","source":"Environmental science and pollution research international","url":"https://pubmed.ncbi.nlm.nih.gov/30062542","citation_count":17,"is_preprint":false},{"pmid":"28611499","id":"PMC_28611499","title":"Lactobacillus futsaii CS3, a New GABA-Producing Strain Isolated from Thai Fermented Shrimp (Kung-Som).","date":"2016","source":"Indian journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28611499","citation_count":17,"is_preprint":false},{"pmid":"2899168","id":"PMC_2899168","title":"Psychopharmacological consequences of activation of beta adrenergic receptors by SOM-1122.","date":"1988","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/2899168","citation_count":16,"is_preprint":false},{"pmid":"27907249","id":"PMC_27907249","title":"Grainyhead-like 3 (Grhl3) deficiency in brain leads to altered locomotor activity and decreased anxiety-like behaviors in aged mice.","date":"2017","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/27907249","citation_count":15,"is_preprint":false},{"pmid":"28058488","id":"PMC_28058488","title":"Inhibition of Staphylococcus aureus in vitro by bacteriocinogenic Lactococcus lactis KTH0-1S isolated from Thai fermented shrimp (Kung-som) and safety evaluation.","date":"2017","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28058488","citation_count":15,"is_preprint":false},{"pmid":"35857527","id":"PMC_35857527","title":"Cis-regulatory chromatin loops analysis identifies GRHL3 as a master regulator of surface epithelium commitment.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/35857527","citation_count":14,"is_preprint":false},{"pmid":"34628539","id":"PMC_34628539","title":"Comprehensive characterization of oscillatory signatures in a model circuit with PV- and SOM-expressing interneurons.","date":"2021","source":"Biological cybernetics","url":"https://pubmed.ncbi.nlm.nih.gov/34628539","citation_count":14,"is_preprint":false},{"pmid":"11849359","id":"PMC_11849359","title":"Genotypic and phenotypic characterization of garlic-fermenting lactic acid bacteria isolated from som-fak, a Thai low-salt fermented fish product.","date":"2002","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11849359","citation_count":14,"is_preprint":false},{"pmid":"25079644","id":"PMC_25079644","title":"Biodegradation of pyrene by Phanerochaete chrysosporium and enzyme activities in soils: effect of SOM, sterilization and aging.","date":"2014","source":"Journal of environmental sciences (China)","url":"https://pubmed.ncbi.nlm.nih.gov/25079644","citation_count":13,"is_preprint":false},{"pmid":"22796044","id":"PMC_22796044","title":"Classification of Aurora kinase inhibitors by self-organizing map (SOM) and support vector machine (SVM).","date":"2012","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22796044","citation_count":12,"is_preprint":false},{"pmid":"18535082","id":"PMC_18535082","title":"Hyperbolic SOM-based clustering of DNA fragment features for taxonomic visualization and classification.","date":"2008","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18535082","citation_count":12,"is_preprint":false},{"pmid":"33775911","id":"PMC_33775911","title":"The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity.","date":"2021","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33775911","citation_count":11,"is_preprint":false},{"pmid":"29270747","id":"PMC_29270747","title":"Knockdown of GRHL3 inhibits activities and induces cell cycle arrest and apoptosis of human colorectal cancer cells.","date":"2017","source":"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","url":"https://pubmed.ncbi.nlm.nih.gov/29270747","citation_count":11,"is_preprint":false},{"pmid":"21686262","id":"PMC_21686262","title":"Grhl3 and GEF19 in the front rho.","date":"2010","source":"Small GTPases","url":"https://pubmed.ncbi.nlm.nih.gov/21686262","citation_count":11,"is_preprint":false},{"pmid":"28185545","id":"PMC_28185545","title":"MiRNATIP: a SOM-based miRNA-target interactions predictor.","date":"2016","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/28185545","citation_count":11,"is_preprint":false},{"pmid":"15736037","id":"PMC_15736037","title":"Histological heterogeneity of human glioblastomas investigated with an unsupervised neural network (SOM).","date":"2005","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/15736037","citation_count":11,"is_preprint":false},{"pmid":"34888136","id":"PMC_34888136","title":"GRHL3 Promotes Tumor Growth and Metastasis via the MEK Pathway in Colorectal Cancer.","date":"2021","source":"Analytical cellular pathology (Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/34888136","citation_count":10,"is_preprint":false},{"pmid":"27459192","id":"PMC_27459192","title":"Lack of Association between Missense Variants in GRHL3 (rs2486668 and rs545809) and Susceptibility to Non-Syndromic Orofacial Clefts in a Han Chinese Population.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27459192","citation_count":10,"is_preprint":false},{"pmid":"35858550","id":"PMC_35858550","title":"A striatal SOM-driven ChAT-iMSN loop generates beta oscillations and produces motor deficits.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35858550","citation_count":10,"is_preprint":false},{"pmid":"36442813","id":"PMC_36442813","title":"Identification of a Novel GRHL3/HOPX/Wnt/β-Catenin Proto-oncogenic Axis in Squamous Cell Carcinoma of the Esophagus.","date":"2022","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/36442813","citation_count":9,"is_preprint":false},{"pmid":"36294595","id":"PMC_36294595","title":"Distribution of Kazachstania Yeast in Thai Traditional Fermented Fish (Plaa-Som) in Northeastern Thailand.","date":"2022","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36294595","citation_count":9,"is_preprint":false},{"pmid":"36457487","id":"PMC_36457487","title":"Consistent downregulation of the cleft lip/palate-associated genes IRF6 and GRHL3 in carcinomas.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36457487","citation_count":8,"is_preprint":false},{"pmid":"38980781","id":"PMC_38980781","title":"ProFun-SOM: Protein Function Prediction for Specific Ontology Based on Multiple Sequence Alignment Reconstruction.","date":"2025","source":"IEEE transactions on neural networks and learning systems","url":"https://pubmed.ncbi.nlm.nih.gov/38980781","citation_count":8,"is_preprint":false},{"pmid":"27074760","id":"PMC_27074760","title":"Self-Organizing Map (SOM) and Support Vector Machine (SVM) Models for the Prediction of Human Epidermal Growth Factor Receptor (EGFR/ ErbB-1) Inhibitors.","date":"2016","source":"Combinatorial chemistry & high throughput screening","url":"https://pubmed.ncbi.nlm.nih.gov/27074760","citation_count":8,"is_preprint":false},{"pmid":"31467377","id":"PMC_31467377","title":"Novel computational model of gastrula morphogenesis to identify spatial discriminator genes by self-organizing map (SOM) clustering.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31467377","citation_count":8,"is_preprint":false},{"pmid":"25692291","id":"PMC_25692291","title":"Differences in SOM decomposition and temperature sensitivity among soil aggregate size classes in a temperate grasslands.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25692291","citation_count":8,"is_preprint":false},{"pmid":"24499310","id":"PMC_24499310","title":"Structure-based modeling of dye-fiber affinity with SOM-4D-QSAR paradigm: application to set of anthraquinone derivatives.","date":"2014","source":"Combinatorial chemistry & high throughput screening","url":"https://pubmed.ncbi.nlm.nih.gov/24499310","citation_count":8,"is_preprint":false},{"pmid":"14652875","id":"PMC_14652875","title":"A SOM projection technique with the growing structure for visualizing high-dimensional data.","date":"2003","source":"International journal of neural systems","url":"https://pubmed.ncbi.nlm.nih.gov/14652875","citation_count":8,"is_preprint":false},{"pmid":"39548236","id":"PMC_39548236","title":"Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39548236","citation_count":7,"is_preprint":false},{"pmid":"32581582","id":"PMC_32581582","title":"Expression Analysis of GRHL3 and PHLDA3 in Head and Neck Squamous Cell Carcinoma.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32581582","citation_count":7,"is_preprint":false},{"pmid":"36248848","id":"PMC_36248848","title":"Transcriptional states of CAR-T infusion relate to neurotoxicity - lessons from high-resolution single-cell SOM expression portraying.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36248848","citation_count":7,"is_preprint":false},{"pmid":"22591483","id":"PMC_22591483","title":"In silico prediction of cytochrome P450-mediated site of metabolism (SOM).","date":"2013","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/22591483","citation_count":7,"is_preprint":false},{"pmid":"31332962","id":"PMC_31332962","title":"Genetic variants in GRHL3 and risk for neural tube defects: A case-control and case-parent triad/control study.","date":"2019","source":"Birth defects research","url":"https://pubmed.ncbi.nlm.nih.gov/31332962","citation_count":6,"is_preprint":false},{"pmid":"37385508","id":"PMC_37385508","title":"Water-soluble organic carbon (WSOC) from vegetation fire and its differences from WSOC in natural media: Spectral comparison and self-organizing maps (SOM) classification.","date":"2023","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/37385508","citation_count":6,"is_preprint":false},{"pmid":"26797800","id":"PMC_26797800","title":"Clinical significance of GRHL3 expression in diffuse large B cell lymphoma.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26797800","citation_count":5,"is_preprint":false},{"pmid":"34570762","id":"PMC_34570762","title":"Grhl3 promotes retention of epidermal cells under endocytic stress to maintain epidermal architecture in zebrafish.","date":"2021","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34570762","citation_count":5,"is_preprint":false},{"pmid":"24965867","id":"PMC_24965867","title":"Distribution of peptidergic populations in the human dentate gyrus (somatostatin [SOM-28, SOM-12] and neuropeptide Y [NPY]) during postnatal development.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24965867","citation_count":5,"is_preprint":false},{"pmid":"37171680","id":"PMC_37171680","title":"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.","date":"2023","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37171680","citation_count":5,"is_preprint":false},{"pmid":"27467876","id":"PMC_27467876","title":"Classification of Aurora-A Kinase Inhibitors Using Self-Organizing Map (SOM) and Support Vector Machine (SVM).","date":"2011","source":"Molecular informatics","url":"https://pubmed.ncbi.nlm.nih.gov/27467876","citation_count":5,"is_preprint":false},{"pmid":"32049322","id":"PMC_32049322","title":"ShinySOM: graphical SOM-based analysis of single-cell cytometry data.","date":"2020","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32049322","citation_count":4,"is_preprint":false},{"pmid":"9387336","id":"PMC_9387336","title":"[Expression of somatostatin mRNA and coexistence of SOM mRNA and 5-HT in nucleus raphe dorsalis following noxious stimulation and electroacupuncture analgesia].","date":"1996","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/9387336","citation_count":4,"is_preprint":false},{"pmid":"40507883","id":"PMC_40507883","title":"QTL Mapping and Developing KASP Markers for High-Temperature Adult-Plant Resistance to Stripe Rust in Argentinian Spring Wheat William Som (PI 184597).","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40507883","citation_count":4,"is_preprint":false},{"pmid":"17281313","id":"PMC_17281313","title":"Prediction Models for DNA Transcription Termination Based on SOM Networks.","date":"2005","source":"Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference","url":"https://pubmed.ncbi.nlm.nih.gov/17281313","citation_count":4,"is_preprint":false},{"pmid":"34255421","id":"PMC_34255421","title":"Association analysis of SNPs in GRHL3, FAF1, and KCNJ2 with NSCPO sub-phenotypes in Han Chinese.","date":"2021","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/34255421","citation_count":3,"is_preprint":false},{"pmid":"34220153","id":"PMC_34220153","title":"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.","date":"2021","source":"Contemporary clinical dentistry","url":"https://pubmed.ncbi.nlm.nih.gov/34220153","citation_count":3,"is_preprint":false},{"pmid":"20233261","id":"PMC_20233261","title":"Phylogenetic diversity of gene sequences isolated from the rumen as analysed using a self-organizing map (SOM).","date":"2010","source":"Journal of applied microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20233261","citation_count":3,"is_preprint":false},{"pmid":"38383230","id":"PMC_38383230","title":"The GRHL3-regulated long non-coding RNA lnc-DC modulates keratinocytes differentiation by interacting with IGF2BP2 and up-regulating ZNF750.","date":"2024","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/38383230","citation_count":2,"is_preprint":false},{"pmid":"19521786","id":"PMC_19521786","title":"Impact of Octreotide and SOM-230 on liver metastasis and hepatic lipidperoxidation in ductal pancreatic adenocarcinoma in Syrian Hamster.","date":"2009","source":"Clinical & experimental metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/19521786","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47891,"output_tokens":7034,"usd":0.124591,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16305,"output_tokens":6067,"usd":0.1166,"stage2_stop_reason":"end_turn"},"total_usd":0.241191,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Protein interaction studies (pulldown/co-IP), phylogenetic and domain analysis, alternative splicing characterization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — protein interaction pulldown from single lab, supported by domain analysis across multiple isoforms\",\n      \"pmids\": [\"12549979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Gene targeting (knockout mice), genetic complementation, mapping studies\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic complementation, knockout phenotype, and mapping in a single rigorous study with multiple orthogonal genetic approaches\",\n      \"pmids\": [\"14608380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Gene knockout (null mice), gene expression analysis, ultrastructural analysis\",\n      \"journal\": \"Organogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype with defined molecular target, single lab\",\n      \"pmids\": [\"19521564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Protein interaction (co-IP), genetic interaction (double knockout mice), barrier function assays, histology\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic interaction confirmed by double KO, co-expression and protein interaction in same study\",\n      \"pmids\": [\"16949565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mice (eye-open phenotype), organ culture, immunofluorescence, western blot (phospho-EGFR, phospho-ERK), TGFα rescue experiment\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO phenotype with defined pathway placement, ligand rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"18485343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical interaction (co-IP), double knockout mouse genetics, in vitro scratch assay, immunofluorescence, western blot\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction plus double-KO genetic confirmation, multiple phenotypic readouts\",\n      \"pmids\": [\"18619436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Knockout mice, genome-wide expression profiling, ChIP (direct promoter binding), reporter assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP evidence for target gene, KO phenotype, multiple orthogonal methods in single study\",\n      \"pmids\": [\"19494835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice, ChIP (PTEN as direct target), Pten rescue experiment, tumor assays\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct target identified by ChIP, genetic rescue fully abrogates phenotype, conditional KO\",\n      \"pmids\": [\"22094257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown in endothelial cells, migration assay, apoptosis assay, western blot (phospho-Akt, phospho-eNOS)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, siRNA KD with defined molecular readouts, multiple phenotypic assays\",\n      \"pmids\": [\"21856281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"miRNA profiling, ChIP (miR-21 promoter binding by GRHL3), luciferase reporter assay, overexpression/knockdown in keratinocytes, tumor xenograft assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding by ChIP plus functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"22614019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq, gene expression profiling, genome-wide analysis in epidermis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq genome-wide evidence for Trithorax recruitment, single lab\",\n      \"pmids\": [\"22829784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Sequencing of VWS families, zebrafish functional assay, mouse knockout/double heterozygote genetic epistasis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional zebrafish assay, mouse genetics with epistasis analysis, multiple orthogonal approaches\",\n      \"pmids\": [\"24360809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice, imiquimod model, ChIP-Seq, gene expression profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP-Seq, expression profiling, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"25347468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Rodent NASH models, transgenic mice (leptin/leptin receptor null), western blot, qRT-PCR, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple mouse models with consistent results, mechanistic link through miR-21/Grhl3/NOS3 axis, single lab\",\n      \"pmids\": [\"25658689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Comparative expression profiling between SE and NE lineages, canonical Wnt pathway manipulation, Grhl3 expression analysis in neural plate border\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression profiling combined with pathway analysis, single lab, mechanistic placement downstream of Wnt\",\n      \"pmids\": [\"26288816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP-seq (GRHL3, H3K27ac), ATAC-seq, gene expression profiling in human keratinocytes (differentiated vs. migrating)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq and chromatin profiling with multiple orthogonal methods, functional implications in two cell states\",\n      \"pmids\": [\"28445475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"BRD4 ChIP-seq, eRNA analysis, EGFR/AKT and Src inhibitor treatments, siRNA knockdown of BRD4\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with functional pathway inhibitor experiments, single lab\",\n      \"pmids\": [\"27980063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Embryoid body differentiation in vitro, immunofluorescence (subcellular localization), VANGL2/CELSR1 expression analysis, Wnt signaling pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by imaging with functional consequence, mechanistic link to PCP components, single lab\",\n      \"pmids\": [\"30283008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"GRHL3 siRNA knockdown (human keratinocytes), cytokine array, mouse Grhl3-KO skin analysis (immunohistochemistry, flow cytometry), 5-ASA rescue experiment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cytokine array plus KO mouse confirmation, single lab, two experimental systems\",\n      \"pmids\": [\"30341279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetics (Irf6 overexpression and loss-of-function), gene expression analysis (qRT-PCR, in situ hybridization), human spina bifida sequencing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with gain- and loss-of-function, single lab\",\n      \"pmids\": [\"30689861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell RNA-seq, RNA velocity analysis, GRHL3 conditional knockout mice, gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — scRNA-seq with RNA velocity plus conditional KO, multiple orthogonal methods, identifies Wnt suppression mechanism\",\n      \"pmids\": [\"33116143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice (Grhl3-cKO), ATAC-seq, wound healing assay, E-cadherin and FSCN1 expression analysis, ChIP/motif analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ATAC-seq chromatin accessibility, conditional KO, defined GRHL3/FSCN1/E-cadherin pathway, multiple orthogonal methods\",\n      \"pmids\": [\"34494554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR knockout of IpA site, CPSF knockdown, RNA-seq, protein interaction (CPSF-HNRNPA3 interaction), targeted genetic screen\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR-based functional validation, protein interaction, RNA-seq, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33469008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Live imaging in zebrafish, transcriptome analysis, genetic interaction studies (grhl3 and myoVb), E-cadherin expression analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with functional consequence, genetic interaction, transcriptome, single lab\",\n      \"pmids\": [\"34570762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"hESC differentiation, Hi-C (cis-regulatory chromatin loop analysis), ATAC-seq, ChIP-seq, RNA-seq, GRHL3 overexpression\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genome-wide chromatin methods plus functional overexpression, positive feedback loop validated\",\n      \"pmids\": [\"35857527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Grhl3 knockout mice, RNA-seq, ChIP-seq, ChIP-PCR, immunohistochemistry, patient samples\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse, ChIP-seq/ChIP-PCR direct target evidence, RNA-seq, patient validation\",\n      \"pmids\": [\"36442813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Single-cell RNA-seq, immunohistochemistry, spatial transcriptomics, functional experiments in keratinocytes\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq with functional validation, single lab, consistent with differentiation-state model\",\n      \"pmids\": [\"39548236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CUT&RUN assay (GRHL3 binding to lnc-DC promoter), RIP assay (lnc-DC/IGF2BP2 interaction), RNA stability assay, siRNA knockdown, overexpression, whole transcriptome sequencing\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&RUN for direct binding, RIP for RNA-protein interaction, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"38383230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"GPX4 overexpression in HCC cells, nuclear fractionation, ChIP/promoter binding assay, functional metastasis assays, FACS-based ROS analysis\",\n      \"journal\": \"Translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter binding domain identified, functional assays, single lab\",\n      \"pmids\": [\"38797432\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRHL3 is an epithelial transcription factor that acts as a master regulator of surface epithelium commitment, epidermal differentiation, and barrier integrity by directly binding and activating differentiation gene targets (including PTEN, TGase 1, uroplakin II, FSCN1, HOPX, APOBEC3A) and repressing proliferative/stem cell programs (including miR-21, Wnt signaling); it dimerizes with other GRHL family members and functionally cooperates with LMO4 to regulate neural tube closure, eyelid closure, and wound repair through the EGFR/ERK and Rho GTPase/actin pathways, while its expression is post-transcriptionally suppressed in progenitors via CPSF-HNRNPA3-mediated intronic polyadenylation and transcriptionally regulated upstream by the TFAP2A-IRF6-Wnt signaling axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #2, #24]. 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 [#14, #24]. 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 [#2, #6, #26], while simultaneously restraining stem/progenitor and proliferative programs by suppressing Wnt signaling and controlling the stem-to-transition cell transition [#20]. 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 [#10, #15]. 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/\\u03b2-catenin in esophageal carcinoma [#7, #9, #25]. During wound repair GRHL3 cooperates genetically and biochemically with the LIM-only protein LMO4 and acts upstream of TGF\\u03b1 in the EGFR/ERK pathway to drive actin-based keratinocyte migration, and activates FSCN1 to loosen adherens junctions for collective migration [#3, #4, #5, #21]. Coding mutations in GRHL3 cause Van der Woude syndrome, and GRHL3 acts in a TFAP2A-IRF6 regulatory pathway during palatogenesis and neurulation [#11, #19]. GRHL3 abundance is itself controlled post-transcriptionally in progenitors through CPSF-HNRNPA3-mediated intronic polyadenylation that suppresses full-length transcript to prevent premature differentiation [#22].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing GRHL3 as a grainyhead-family transcription factor that selectively heterodimerizes defined the molecular class and partner specificity underlying its activity.\",\n      \"evidence\": \"Protein interaction pulldowns and domain/phylogenetic analysis across isoforms\",\n      \"pmids\": [\"12549979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct DNA target or functional consequence of dimerization shown\", \"Dimerization assayed in vitro without in vivo confirmation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knockout mice, genetic complementation, and mapping\",\n      \"pmids\": [\"14608380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in neural tube not identified here\", \"Mechanism of closure failure unresolved at the molecular level\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Linking Grhl3 loss to barrier failure via Transglutaminase 1 provided the first direct differentiation target and a mechanistic basis for the skin phenotype.\",\n      \"evidence\": \"Null mice, expression analysis, ultrastructural lipid analysis\",\n      \"pmids\": [\"19521564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter binding to TGase1 not demonstrated in this study\", \"Single lab\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating biochemical and genetic interaction with LMO4 revealed that GRHL3 acts in a cofactor complex to drive epidermal terminal differentiation.\",\n      \"evidence\": \"Co-IP and double-knockout mouse genetics with barrier assays\",\n      \"pmids\": [\"16949565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GRHL3-LMO4 interaction unknown\", \"Whether LMO4 alters target-gene selection not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placing Get1/Grhl3 upstream of TGF\\u03b1 in the EGFR/ERK pathway and showing LMO4-dependent ERK activation connected GRHL3 to actin-driven keratinocyte migration during eyelid closure and wound repair.\",\n      \"evidence\": \"Knockout mice (eye-open), organ culture, phospho-EGFR/ERK westerns, TGF\\u03b1 rescue, scratch assays\",\n      \"pmids\": [\"18485343\", \"18619436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional target driving TGF\\u03b1/ERK not pinpointed\", \"Cytoskeletal effectors downstream not fully mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Knockout mice, expression profiling, ChIP, reporter assays\",\n      \"pmids\": [\"19494835\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Histone-modification context of selective binding only partially defined\", \"Cofactor requirements at the uroplakin promoter unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying PTEN as a direct GRHL3 target whose restoration abrogates SCC established GRHL3 as a tumor suppressor restraining PI3K/AKT/mTOR signaling.\",\n      \"evidence\": \"Conditional knockout, ChIP, Pten genetic rescue, tumor assays\",\n      \"pmids\": [\"22094257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other GRHL3 targets contribute to SCC suppression not resolved here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing GRHL3 drives endothelial Akt/eNOS phosphorylation for NO-dependent migration and anti-apoptosis broadened its role beyond epithelium.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells, migration/apoptosis assays, phospho-westerns\",\n      \"pmids\": [\"21856281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional targets in endothelium not identified\", \"siRNA only, single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP/luciferase for miR-21, miRNA profiling, xenografts; ChIP-seq and expression profiling for Trithorax recruitment\",\n      \"pmids\": [\"22614019\", \"22829784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Trithorax complex recruitment to GRHL3 sites not defined\", \"How GRHL3 switches between activation and repression unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"VWS family sequencing, zebrafish functional assay, mouse double-heterozygote epistasis\",\n      \"pmids\": [\"24360809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Periderm target genes of GRHL3 not identified\", \"Penetrance determinants of cleft palate unexplained\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional knockout, imiquimod model, ChIP-Seq, expression profiling\",\n      \"pmids\": [\"25347468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of context-specific binding not defined\", \"Cofactors distinguishing development vs repair targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Wnt pathway manipulation with expression profiling; rodent NASH and leptin-null models with westerns/qRT-PCR\",\n      \"pmids\": [\"26288816\", \"25658689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Wnt-responsive elements controlling Grhl3 not mapped\", \"Causal vs correlative role in NASH endothelium not fully separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"GRHL3 and H3K27ac ChIP-seq, ATAC-seq in keratinocyte states; BRD4 ChIP-seq with EGFR/AKT/Src inhibitors\",\n      \"pmids\": [\"28445475\", \"27980063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism redirecting GRHL3 to super-enhancers vs promoters unknown\", \"Functional cooperation with REST during migration only partially defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Embryoid body differentiation with subcellular imaging; siRNA knockdown, cytokine array, KO mouse immunophenotyping, 5-ASA rescue\",\n      \"pmids\": [\"30283008\", \"30341279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GRHL3 cytoplasmic relocalization unknown\", \"Whether TARC regulation is direct not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"Irf6 gain- and loss-of-function mice, expression analysis, human spina bifida sequencing\",\n      \"pmids\": [\"30689861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct regulatory connections among TFAP2A, IRF6, and GRHL3 not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"scRNA-seq with RNA velocity and conditional knockout mice\",\n      \"pmids\": [\"33116143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Wnt-pathway targets in stem cells not identified\", \"Switch-controlling cofactors undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional KO + ATAC-seq + wound assays (FSCN1); zebrafish live imaging/genetics; CRISPR IpA-site knockout, CPSF knockdown, RNA-seq, protein interaction\",\n      \"pmids\": [\"34494554\", \"34570762\", \"33469008\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How HNRNPA3 directs CPSF specifically to the GRHL3 intron not fully resolved\", \"Signals triggering the IpA switch during differentiation unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating GRHL3 sufficiency to initiate surface-epithelium fate (priming chromatin, BMP4 feedback) and direct HOPX activation limiting Wnt/\\u03b2-catenin in ESCC unified its roles in fate commitment and tumor suppression.\",\n      \"evidence\": \"hESC differentiation with Hi-C/ATAC-seq/ChIP-seq/RNA-seq and overexpression; conditional KO with ChIP-seq/ChIP-PCR and patient samples\",\n      \"pmids\": [\"35857527\", \"36442813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pioneer-factor mechanism of chromatin priming not mechanistically dissected\", \"How GRHL3 activity is restrained in carcinoma cells unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"39548236\", \"38383230\", \"38797432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Consequence of expanded APOBEC3A expression to proliferating SCC cells not fully tested\", \"Mechanism by which nuclear GPX4 silences the GRHL3 promoter incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GRHL3 selects context-specific target sets and switches between gene activation and repression across cell states remains the central unresolved mechanistic question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 6, 7, 9, 25, 26, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [6, 7, 9, 25, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7, 15, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 11, 14, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 9, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 11, 25, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 14, 20]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10, 15, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GRHL1\", \"GRHL2\", \"LMO4\", \"REST\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}