Affinage

GRHL2

Grainyhead-like protein 2 homolog · UniProt Q6ISB3

Length
625 aa
Mass
71.1 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRHL2 is a CP2/grainyhead-type epithelial transcription factor that binds directly to promoters and enhancers of epithelial genes to establish and maintain epithelial identity across diverse epithelia (PMID:26887977, PMID:30017589). It acts as a master suppressor of epithelial-to-mesenchymal transition: GRHL2 directly activates the miR-200b/a family and the EMT-suppressors OVOL1/2 while directly repressing ZEB1, embedding it in the miR-200–ZEB1 double-negative feedback loop, such that genetic inactivation of Zeb1 rescues palatal and facial defects in Grhl2-null embryos (PMID:26887977, PMID:32005677, PMID:23814079). GRHL2 enforces these states epigenetically, with its loss provoking gain of H3K27me3, loss of active H3K4me3/H3K27ac marks, and CpG methylation at epithelial gene loci (PMID:26887977, PMID:31372511), and its activation of a subset of epithelial enhancers during the naive-ESC-to-EpiLC transition occurs through enhancer switching that preserves target gene transcription (PMID:30017589). Through direct regulation of junctional and barrier genes—claudins, EpCAM, SPINT1, p63, and the EDC differentiation cluster—it is required for epithelial barrier function and morphogenesis in the cochlea, airway, lung, kidney collecting duct, placenta, and salivary gland (PMID:21610158, PMID:29237740, PMID:26527742, PMID:25758223, PMID:30193734, PMID:26085095, PMID:23254293). In the surface ectoderm GRHL2 tunes biomechanical properties: its loss shifts ectoderm to a neuroepithelial identity with actomyosin disorganization, while its excess produces a hyper-epithelial, mechanically stiff state, both of which impair neural tube closure (PMID:31171776, PMID:36843855). GRHL2 functions as a context-dependent nuclear-receptor co-regulator, pre-bound at active enhancers where it cooperates with FOXA1, p300, and pS118-phosphorylated ERα in breast cancer and with the androgen receptor in prostate cancer (PMID:36036613, PMID:31084623, PMID:28473532). Its activity is modulated post-translationally by p38α/β-driven phosphorylation at T164 that stimulates K159 SUMOylation, and by self-aggregation into repressive subnuclear structures (PMID:40889682). GRHL2 dysfunction causes human disease across its dose range: loss-of-function mutations cause progressive sensorineural hearing loss (DFNA28) and biallelic mutations cause an autosomal-recessive ectodermal dysplasia syndrome, while ectopic gain-of-function regulatory variants drive aberrant mesenchymal-to-epithelial transition in corneal endothelium (PPCD4) (PMID:12393799, PMID:23813623, PMID:25152456, PMID:29499165).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2002 High

    Established GRHL2 as a disease gene by linking a truncating mutation to dominant hearing loss, implicating it in cochlear epithelial function before its biochemical role was known.

    Evidence Positional cloning, candidate-gene sequencing and expression analysis in a DFNA28 family

    PMID:12393799 PMID:23813623

    Open questions at the time
    • Did not define direct transcriptional targets or DNA-binding mechanism
    • Cochlear-specific target genes not identified
  2. 2011 High

    Defined GRHL2 as a direct transcriptional activator of junctional genes and demonstrated functional conservation, showing it builds apical junctional complexes through cldnb and epcam.

    Evidence Zebrafish insertional mutant, enhancer ChIP, and mRNA rescue with wild-type versus DFNA28-mutant human GRHL2

    PMID:21610158

    Open questions at the time
    • Did not address mammalian target repertoire genome-wide
    • Cofactors at junctional enhancers unknown
  3. 2011 High

    Showed GRHL2 dosage is the critical variable for morphogenesis, establishing that excess Grhl2 causally produces neural tube defects.

    Evidence Bidirectional mouse genetics combining gain-of-function (Axd) and loss-of-function Grhl2 alleles

    PMID:21262862

    Open questions at the time
    • Mechanism by which excess GRHL2 blocks closure not yet defined (resolved later in #22)
  4. 2012 Medium

    Linked GRHL2 to chromatin-level gene control, showing it restrains differentiation by blocking histone demethylase recruitment and maintaining repressive H3K27me3.

    Evidence ChIP and expression profiling with lentiviral overexpression in primary keratinocytes

    PMID:23254293

    Open questions at the time
    • Direct versus indirect Jmjd3 exclusion not biochemically resolved
    • Single lab, one cell type
  5. 2013 Medium

    Identified the GRHL2–ZEB1 double-negative feedback loop and a direct activating target (ERBB3), placing GRHL2 at the center of epithelial-state control.

    Evidence Expression cloning, shRNA knockdown, microarray and phylogenetic footprinting in breast cancer cells

    PMID:23814079

    Open questions at the time
    • miR-200 intermediary not yet shown to mediate ZEB1 repression (resolved in #9, #25)
    • Single lab
  6. 2013 Medium

    Connected GRHL2 to telomerase regulation in cancer by identifying it as an hTERT promoter binder required for telomerase activity.

    Evidence Promoter pulldown-mass spectrometry, shRNA knockdown, luciferase and telomerase assays in oral SCC

    PMID:19015635

    Open questions at the time
    • Cofactors at hTERT promoter undefined
    • Generalizability beyond oral SCC untested
  7. 2015 High

    Generalized GRHL2's role to ciliated and barrier epithelia and to placental development through direct binding of ciliogenesis genes and Spint1.

    Evidence Conditional mouse KO, human CRISPR editing, organoid assays, and placental ChIP-seq with tissue-specific rescue

    PMID:25758223 PMID:26527742

    Open questions at the time
    • Combinatorial cofactors directing tissue-specific target choice unresolved
  8. 2015 Medium

    Defined a GRHL2–p63 reciprocal feedback loop reinforcing epithelial identity in keratinocytes.

    Evidence ChIP, siRNA/overexpression and histone-mark analysis

    PMID:26085095

    Open questions at the time
    • Mechanism coupling the two factors at chromatin not resolved
    • Single lab
  9. 2016 High

    Provided genome-wide proof that GRHL2 directly activates miR-200b/a and E-cadherin and maintains the epithelial state through the miR-200–ZEB1 axis epigenetically.

    Evidence ChIP-seq, expression microarray, H3K27me3 analysis and shRNA knockdown in ovarian cancer

    PMID:26887977

    Open questions at the time
    • Enzymes depositing H3K27me3 after GRHL2 loss not identified
  10. 2017 Medium

    Extended GRHL2 to nuclear-receptor co-regulation, showing it is an androgen-receptor coregulator forming a positive AR feedback loop.

    Evidence Proteomic AR-coregulator identification, ChIP co-localization and knockdown in prostate cancer models

    PMID:28473532

    Open questions at the time
    • Direct physical AR–GRHL2 contact versus tethering unresolved
    • Single lab
  11. 2017 Medium

    Showed GRHL2 directly controls cytoskeletal-migration (RhoG) and proliferation (FoxM1B) programs, and links to HPV-driven oral carcinogenesis.

    Evidence ChIP, luciferase reporters, retroviral E6/E7 expression and Grhl2 conditional KO with 4-NQO carcinogenesis

    PMID:28979695 PMID:29443638

    Open questions at the time
    • Opposing migration-suppressing/proliferation-promoting outputs not mechanistically reconciled
  12. 2018 High

    Revealed GRHL2 acts via the MAPK pathway to suppress TGF-β signaling, a mechanism distinct from its direct transcriptional targeting, and is required for oral tumorigenesis.

    Evidence Grhl2 conditional KO + 4-NQO model, Western blotting, and pharmacological Erk/JNK inhibition

    PMID:29735981

    Open questions at the time
    • How GRHL2 activates Erk/JNK mechanistically not defined
    • Direct kinase-pathway targets unknown
  13. 2018 High

    Demonstrated that GRHL2 maintains transcription through enhancer switching, activating alternative epithelial enhancers during the ESC-to-EpiLC transition.

    Evidence Conditional deletion/overexpression with H3K27ac ChIP-seq, ATAC-seq, RNA-seq and GRHL2 ChIP-seq

    PMID:30017589

    Open questions at the time
    • Factors recruited to GRHL2-dependent alternative enhancers not identified
  14. 2018 Medium

    Connected GRHL2 dosage disease to molecular pathology, showing ectopic GRHL2 expression drives MET in corneal endothelium (PPCD4) and that GRHL2/GRHL3 dimers act additively in NTDs.

    Evidence Whole-genome sequencing with reporter assays and patient IHC; transgenic dimerization/epistasis genetics

    PMID:29499165 PMID:30189017 PMID:30194919

    Open questions at the time
    • Structural basis of GRHL2/GRHL3 dimer specificity unresolved
    • How ectopic enhancer variants gain activity not fully defined
  15. 2019 High

    Showed GRHL2 controls the EMT epigenome directly, with its loss causing DNA methylation gain and nucleosomal remodeling at epithelial loci.

    Evidence Multi-histone-mark ChIP-seq, DNA methylation profiling and shRNA knockdown in ovarian cancer

    PMID:31372511

    Open questions at the time
    • Recruitment of methylation/remodeling machinery by GRHL2 status not mechanistically isolated
  16. 2019 Medium

    Established GRHL2 as a pre-bound enhancer co-regulator of ERα and FOXA1 in breast cancer, defining a targetable LYPD3/AGR2 pathway in endocrine resistance.

    Evidence VULCAN/ChIP-seq cistromics, eRNA measurement, knockdown, and in vivo antibody inhibition

    PMID:30455249 PMID:31084623 PMID:31644911

    Open questions at the time
    • Direct GRHL2–ERα physical interaction not biochemically confirmed
    • Context-dependent enhance/antagonize switch undefined
  17. 2019 High

    Defined the biomechanical basis of GRHL2 dosage control in neural tube closure, showing it tunes ectoderm identity and actomyosin-dependent mechanical stress.

    Evidence Reciprocal gain/loss mouse embryos with live imaging, laser ablation and myosin inhibition

    PMID:31171776

    Open questions at the time
    • Direct GRHL2 targets controlling actomyosin not enumerated
  18. 2019 High

    Demonstrated GRHL2 is required for epithelial barrier function in the kidney collecting duct and salivary gland through direct regulation of claudins and SPINT1.

    Evidence Conditional KO mouse with electrophysiology and urine assays; ChIP-PCR and recombinant SPINT1 rescue in salivary gland

    PMID:29237740 PMID:30193734

    Open questions at the time
    • Full claudin target set and tissue-specific regulatory logic not defined
  19. 2020 High

    Established GRHL2 as the upstream node of the OVOL/miR-200/ZEB1 EMT circuit in vivo by rescuing Grhl2-null facial/palatal defects through Zeb1 inactivation.

    Evidence Grhl2/Zeb1 compound-mutant mouse genetics with direct-target expression analysis

    PMID:32005677

    Open questions at the time
    • Relative contributions of OVOL versus miR-200 arms not quantified
  20. 2020 Medium

    Showed GRHL2 governs reversible EMT–MET dynamics during wound healing via the miR-200/ZEB1 axis, with loss promoting fibrosis.

    Evidence Knockdown/overexpression in wound-healing mouse model with miR-200 rescue

    PMID:39402063

    Open questions at the time
    • Signals driving dynamic GRHL2 down/upregulation during healing unknown
  21. 2022 High

    Resolved GRHL2 as a pioneer-like pre-bound factor required for maximal pS118-ER recruitment, integrating it with FOXA1 and p300 at active enhancers controlling migration.

    Evidence Combined GRHL2/pS118-ER/FOXA1/p300/histone ChIP-seq, RNA-seq and migration assays

    PMID:36036613

    Open questions at the time
    • Determinants of locus-specific enhancement versus antagonism still undefined
  22. 2023 Medium

    Defined GRHL2/AP2α cooperative and antagonistic chromatin logic in surface-ectoderm fate commitment and showed ectodermal dysplasia variants disrupt this binding.

    Evidence Multi-omic ATAC/ChIP/RNA-seq during human SE differentiation with knockdown and variant testing

    PMID:36843855

    Open questions at the time
    • Physical GRHL2–AP2α interaction not shown
    • Single lab
  23. 2025 Medium

    Identified post-translational control of GRHL2: a p38-driven T164 phosphorylation–K159 SUMOylation axis and self-aggregation as activity-modulating mechanisms.

    Evidence Yeast two-hybrid, site-directed mutagenesis, p38 inhibition, PIAS overexpression and structural/IHC analysis

    PMID:40889682

    Open questions at the time
    • Functional consequence of SUMOylation on specific target genes not mapped
    • Aggregation triggers in vivo unknown
  24. 2025 Medium

    Connected GRHL2 to immune-microenvironment control through an MLL3 complex/IRF1 chemokine axis and a MORF4L2-NuA4-CSF1 macrophage-polarization axis affecting immunotherapy response.

    Evidence Co-IP/proteomics, ChIP, RNA-seq, organoid models, and in vivo ICB/CSF1R inhibition experiments

    PMID:39780291 PMID:39964485

    Open questions at the time
    • Direct MLL3 and MORF4L2 binding interfaces undefined
    • Single lab per axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRHL2 selects among its thousands of binding sites in different tissues, and how its post-translational modifications and cofactor partnerships dictate activation versus repression at a given locus, remains unresolved.
  • No unifying model linking SUMOylation/phosphorylation state to locus-specific output
  • Determinants of context-dependent co-activation versus antagonism with ERα/AP2α unknown
  • Structural basis of DNA recognition and dimerization not resolved in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
AREP300ESR1FOXA1GRHL3MLL3TFAP2A
Complex memberships
GRHL2/GRHL3 dimerMLL3/GRHL2 complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 A frameshift mutation (1609-1610insC) in GRHL2 (then called TFCP2L3) causes premature translation termination and autosomal dominant progressive sensorineural hearing loss (DFNA28); GRHL2 is expressed in epithelial cells lining the cochlear duct. Linkage analysis, candidate gene sequencing, Northern blot, in situ hybridization Human molecular genetics High 12393799 23813623
2011 Zebrafish Grhl2b directly binds enhancers of claudin b (cldnb) and epcam and promotes their expression; loss of Grhl2b abolishes these junction proteins, disrupts apical junctional complexes in otic epithelium, and causes enlarged otocysts, absent otoliths, and deafness. Co-injection of cldnb + epcam mRNA largely rescues the phenotype; wild-type human GRHL2 mRNA (but not the DFNA28 mutant) also rescues, confirming functional conservation. Tol2 transposon insertional mutant, ChIP to enhancers, mRNA rescue injection, genetic complementation with human wild-type vs. mutant GRHL2 Human molecular genetics High 21610158
2011 Over-expression of Grhl2 in mouse embryos causes spina bifida; genetic reduction of Grhl2 function in Axd over-expressing embryos normalizes spinal neural tube closure, demonstrating that excess Grhl2 is the causal mutation. Linkage mapping, expression analysis, genetic rescue cross (Grhl2-null × Axd heterozygotes), loss-of-function mouse model Human molecular genetics High 21262862
2012 GRHL2 inhibits keratinocyte differentiation through epigenetic repression: ChIP shows GRHL2 occupies promoters of epidermal differentiation complex (EDC) genes (IVL, KRT1, FLG, LCEs, SPRRs); GRHL2 binding prevents recruitment of histone demethylase Jmjd3 and increases H3K27me3 levels at EDC gene promoters. ChIP, gene expression profiling, lentiviral overexpression in NHEK cells Cell death & disease Medium 23254293
2013 GRHL2 transcriptionally activates ERBB3 (HER3): GRHL2 knockdown or dominant-negative GRHL2 reduces ERBB3 expression in breast cancer cells; phylogenetic footprinting and microarray identify ERBB3 as a direct target. GRHL2 and ZEB1 form a double-negative regulatory feedback loop: GRHL2 directly represses ZEB1 and ZEB1 directly suppresses GRHL2. Retrovirus cDNA expression cloning, shRNA knockdown, microarray, phylogenetic footprinting, dominant-negative constructs The Journal of biological chemistry Medium 23814079
2013 GRHL2 binds the hTERT promoter (identified by promoter magnetic precipitation + mass spectrometry) and its knockdown reduces hTERT promoter activity and telomerase activity in oral squamous cell carcinoma cells; GRHL2 silencing was uniquely essential among the four identified factors for reducing telomerase activity and cancer cell viability. Promoter magnetic precipitation assay coupled with mass spectrometry, shRNA knockdown, luciferase reporter, telomerase activity assay Oncogene Medium 19015635
2015 GRHL2 directly binds regulatory sites of Notch and ciliogenesis genes (Mcidas, Rfx2, Myb) and is required for ciliated cell differentiation and organoid morphogenesis in airway basal stem cells; loss of GRHL2 inhibits organoid formation and ciliated cell differentiation in both mouse conditional KO and human CRISPR-edited primary basal cells. Conditional gene deletion, CRISPR/Cas9 editing in primary human basal cells, organoid culture, GRHL2 regulatory site identification The Journal of cell biology High 26527742
2015 GRHL2 ChIP-seq in placental tissue identifies 5282 binding sites; integration with placental expression profiles reveals enrichment of GRHL2 binding near downregulated genes in Grhl2-null placentas; GRHL2 directly targets Spint1 (serine protease inhibitor Kunitz type 1), which regulates basal chorionic trophoblast cell integrity and labyrinth formation. Selective Grhl2 deletion in epiblast-derived cells rescues placental defects, confirming a trophectoderm-intrinsic requirement. ChIP-seq in placental tissue, conditional Cre-lox deletion, global Grhl2 knockout, placental expression profiling Development High 25758223
2015 GRHL2 directly binds the p63 promoter (shown by ChIP) and positively regulates p63 expression; reciprocally, p63 isoforms regulate GRHL2 expression, forming a feedback loop that maintains epithelial identity in keratinocytes. GRHL2 knockdown reduces active histone marks at the p63 promoter. ChIP, siRNA knockdown, retroviral overexpression, histone mark analysis The Journal of biological chemistry Medium 26085095
2016 GRHL2 is a direct transcriptional activator of miR-200b/a in ovarian cancer cells: ChIP-seq identifies GRHL2 binding at miR-200b/a and E-cadherin gene promoters/binding sites. GRHL2 loss increases H3K27me3 at these loci. GRHL2 maintains epithelial state via the miR-200–ZEB1–E-cadherin axis; shRNA knockdown of GRHL2 induces EMT. shRNA knockdown, ChIP-seq, gene expression microarray, histone mark (H3K27me3) analysis Scientific reports High 26887977
2017 GRHL2 is an androgen receptor (AR) coregulator: GRHL2 co-localizes with AR on chromatin at specific sites (ChIP), is required for AR expression, enhances AR transcriptional activity, and forms a positive feedback loop (AR regulates GRHL2; GRHL2 maintains AR). GRHL2 also interacts with constitutively active truncated AR variants (ARVs). Novel proteomic technique for AR coregulator identification, ChIP, shRNA/siRNA knockdown in multiple prostate cancer models, gene expression analysis Cancer research Medium 28473532
2017 GRHL2 directly binds the RhoG promoter and decreases RhoG transcriptional activity in non-small cell lung cancer cells, suppressing cell migration while promoting proliferation. ChIP (direct binding to RhoG promoter), GRHL2 overexpression/knockdown, proliferation and migration assays American journal of translational research Medium 28979695
2017 GRHL2 directly binds and activates the FoxM1B gene promoter (luciferase reporter assay); HPV-16 E6 induces FoxM1B in oral keratinocytes in part through GRHL2 upregulation. Grhl2 conditional KO mice exposed to 4-NQO carcinogen fail to develop oral tumors and fail to upregulate FoxM1B, providing in vivo genetic evidence. Luciferase reporter assay, retroviral E6/E7 expression, Grhl2 conditional KO mouse + 4-NQO carcinogen model, shRNA knockdown Journal of dental research Medium 29443638
2018 GRHL2 activates Erk and JNK MAP kinases; GRHL2-mediated suppression of TGF-β signaling is abolished by Erk and JNK inhibitors, indicating GRHL2 suppresses TGF-β through the MAPK pathway. This mechanism is distinct from GRHL2's direct transcriptional regulation of target genes (E-cadherin, hTERT, p63, miR-200 family). Grhl2 conditional KO mice completely fail to develop oral tumors upon 4-NQO exposure, and KO strongly induces TGF-β signaling molecules. Grhl2 conditional KO mouse + 4-NQO carcinogenesis model, Western blot for p-Erk1/2, p-JNK, TGF-β pathway components, pharmacological inhibitors, GRHL2 overexpression/knockdown Oncogenesis High 29735981
2018 GRHL2 is necessary and sufficient to activate an epithelial subset of enhancers during the naive ESC-to-EpiLC transition; many GRHL2 target genes do not change in expression because GRHL2-dependent alternative enhancers become activated to maintain transcription while ESC enhancers diminish (enhancer switching). GRHL2 thereby maintains a subset of the naive pluripotency network via enhancer switching. Conditional GRHL2 deletion/overexpression in ESCs/EpiLCs, H3K27ac ChIP-seq, ATAC-seq, RNA-seq, GRHL2 ChIP-seq Cell stem cell High 30017589
2018 Ectopic non-coding mutations in GRHL2 intronic regulatory regions (c.20+544G>T, c.20+257delT, c.20+133delA) increase transcriptional activity in vitro, causing aberrant GRHL2 expression in corneal endothelial cells (not normally expressing GRHL2). These cells acquire epithelial markers (E-cadherin, Cytokeratin 7), indicating mesenchymal-to-epithelial transition as the pathogenic mechanism of PPCD4. Whole-genome sequencing, in vitro transcriptional activity reporter assays, immunohistochemistry of patient tissue American journal of human genetics Medium 29499165
2018 Grhl2 directly transcriptionally regulates Elf5 (an Ets family transcription factor) in the developing lung: ChIP confirms direct binding at the Elf5 locus. Loss of Grhl2 in lung epithelium leads to impaired ciliated cell differentiation, increased Sox9+ distal tip progenitor cells, and perturbed saccule formation. Conditional lung epithelium-specific Grhl2 deletion, ChIP, transcriptome profiling, comparative genomic analysis Developmental biology Medium 30194919
2018 Grhl2 and Grhl3 can form homodimers and heterodimers; double heterozygous Grhl2/Grhl3 gain-of-function embryos show additive genetic interaction causing severe spina bifida at levels that individually do not cause NTDs. Transgenic BAC overexpression of Grhl3, genetic cross with Grhl2 gain-of-function (Axd) allele, compound heterozygote analysis Human molecular genetics Medium 30189017
2019 GRHL2 knockdown in ovarian cancer cells causes CpG methylation gain and nucleosomal remodeling (reduction of H3K4me3 and H3K27ac; elevation of H3K27me3) at epithelial gene promoters and GRHL2 binding sites, directly linking GRHL2 to the epigenetic regulation of EMT-associated gene silencing. ChIP-seq for five histone marks, DNA methylation profiling, GRHL2 shRNA knockdown, transcriptome profiling Communications biology High 31372511
2019 GRHL2 co-localizes with estrogen receptor α (ERα) at a subset of ER binding sites enriched in GRHL2 motifs; estrogen treatment increases GRHL2 recruitment to pS118-ER sites. GRHL2 knockdown alters ER-associated eRNA expression and strengthens ER binding at active enhancers, indicating GRHL2 is a co-regulator of ER transcriptional output at enhancers. VULCAN (network-based) analysis of ChIP-seq, GRHL2 knockdown, eRNA measurement, ChIP-seq Genome biology Medium 31084623
2019 pS118-phosphorylated ERα occupies sites enriched for GRHL2 motifs; estrogen treatment increases GRHL2 recruitment specifically to pS118-ER sites associated with active enhancers (H3K27ac). In vitro DNA binding assay shows pS118-ER is more commonly associated with direct (vs. indirect) DNA binding events at these sites. ChIP-seq (pS118-ER and total ER), in vitro DNA binding array, estrogen treatment, motif analysis Molecular and cellular biology Medium 30455249
2019 GRHL2 and FOXA1 regulate a common targetable pathway in endocrine therapy-resistant breast cancer, co-regulating LYPD3 expression; inhibiting this pathway with blocking antibodies against LYPD3 or its ligand AGR2 inhibits endocrine therapy-resistant tumor growth in mice. Cellular and mouse models, ChIP/expression discovery platforms, antibody inhibition in vivo Cell reports Medium 31644911
2019 Grhl2 null surface ectoderm undergoes a shift to neuroepithelial identity with ectopic N-cadherin and Sox2 expression, actomyosin disorganization, and diminished resistance to neural fold recoil. Grhl2 over-expression causes a super-epithelial state with upregulated cell junction proteins and actomyosin-dependent increased local mechanical stress that blocks closure progression unless myosin activity is inhibited. Grhl2 null and over-expressing mouse embryos, live imaging, laser ablation of closure point, immunostaining, myosin inhibition Nature communications High 31171776
2019 Grhl2 is required for collecting duct epithelial barrier function: collecting duct-specific deletion of Grhl2 reduces tight junction-associated claudins and transepithelial resistance, impairs renal medullary osmolyte accumulation, and causes diabetes insipidus with failure to concentrate urine. In vitro, Grhl2-deficient collecting duct cells show increased paracellular flux of sodium, chloride, and urea. Collecting duct-specific conditional Grhl2 KO mouse, transepithelial resistance measurement, urine concentration assays, paracellular flux assay in vitro Journal of the American Society of Nephrology High 29237740
2019 Grhl2 directly binds the SPINT1 gene in submandibular salivary gland (confirmed by ChIP-PCR) and regulates its expression; Grhl2 knockdown suppresses E-cadherin and SPINT1 and disorganizes laminin deposition; addition of recombinant SPINT1 rescues the Grhl2-knockdown epithelial development defect. siRNA knockdown in ex vivo SMG culture, ChIP-PCR, rescue with recombinant SPINT1 Biochemical and biophysical research communications Medium 30193734
2020 In Grhl2-null embryos, loss of GRHL2 directly reduces expression of EMT-suppressing transcription factors Ovol1 and Ovol2 (direct GRHL2 targets) and miR-200 family microRNAs (direct GRHL2 targets), resulting in 56-fold upregulation of Zeb1. Genetic inactivation of Zeb1 in Grhl2-null embryos rescues palatal fusion and cleft face, establishing GRHL2 as an upstream regulator of ZEB1 via the Ovol/miR-200 axis in palatogenesis. Grhl2-null mouse embryos, genetic epistasis (Grhl2/Zeb1 compound mutants), expression analysis of direct target genes Disease models & mechanisms High 32005677
2020 GRHL2 regulates EMT-MET dynamics during wound healing; GRHL2 expression is high in normal epidermis, downregulated during EMT, and restored during MET. GRHL2 knockdown in epidermal cells surrounding wounds induces EMT and promotes fibrosis; overexpression in EMT cells partially reverts to epithelial state. The miR-200s/Zeb1 axis mediates GRHL2's control of EMT in keratinocytes. GRHL2 knockdown/overexpression in wound healing mouse model, collagen/fibronectin deposition measurement, miR-200 transfection rescue Cell death & disease Medium 39402063
2020 GRHL2 loss in breast cancer cells triggers NT5E/CD73 ecto-enzyme expression by releasing repression at an intronic NT5E binding site, augmenting extracellular AMP-to-adenosine conversion; increased adenosine mildly increases (not suppresses) CD8 T cell recruitment, and CD73 inhibition prevents this. GRHL2 knockdown in MCF-7 cells, ChIP (GRHL2 binding to NT5E intron), adenosine measurement, CD8 T cell co-culture assay, CD73 inhibition iScience Medium 38706844
2022 GRHL2 is pre-bound to chromatin at pS118-ER/GRHL2 co-occupancy sites before ligand treatment; GRHL2 binding is required for maximal pS118-ER recruitment. Co-occupancy sites are enriched for active enhancer marks (H3K27ac, H3K4me1), FOXA1, and p300. GRHL2 can both enhance and antagonize E2-mediated ER transcription depending on locus; co-regulated genes control cell migration; GRHL2 knockdown combined with estrogen increases migration without changing proliferation. ChIP-seq (GRHL2, pS118-ER, histone marks, FOXA1, p300), RNA-seq, GRHL2 knockdown, migration assay Molecular and cellular biology High 36036613
2023 GRHL2 and AP2α coordinate early surface ectoderm commitment: GRHL2 facilitates AP2α binding to SE loci while AP2α restricts GRHL2 DNA binding away from de novo chromatin contacts. GRHL2 skews cell fate away from neural lineage. Disease-linked ectodermal dysplasia variants directly affect GRHL2/AP2α binding and gene transcription at identified regulatory loci. Multi-omics (ATAC-seq, ChIP-seq, RNA-seq) during human SE differentiation, GRHL2 and AP2α knockdown/overexpression, variant functional testing iScience Medium 36843855
2025 GRHL2 is SUMOylated at lysine 159; SUMOylation enhances GRHL2 transcriptional activity. Phosphorylation of GRHL2 at threonine 164 by p38α/β MAPKs stimulates its SUMOylation. PIAS family SUMO E3 ligases also stimulate GRHL2 SUMOylation. GRHL2 is an intrinsically disordered protein with propensity to form aggresome-like nuclear structures, repressing its activity; subnuclear compartmentalization affects GRHL2 function in breast cancer. Yeast two-hybrid screening for SUMOylation machinery interactors, site-directed mutagenesis (K159 SUMOylation site, T164 phosphorylation site), p38 kinase inhibition, PIAS overexpression, structural analysis, immunohistochemistry The Journal of biological chemistry Medium 40889682
2025 GRHL2 forms a protein complex with MLL3 that regulates the epigenome of upper aerodigestive squamous cell carcinoma; the MLL3/GRHL2 complex promotes a novel MLL3/GRHL2–IRF1 axis driving Th1 chemokine expression and T cell infiltration into the tumor microenvironment, thereby influencing immune checkpoint blockade efficacy. CRISPR-edited cross-species organoid modeling, co-immunoprecipitation/proteomic identification of complex, RNA-seq, ChIP, in vivo ICB therapy experiments The Journal of experimental medicine Medium 39964485
2025 GRHL2 promotes MORF4L2 transcription by binding to the MORF4L2 enhancer region; MORF4L2 acts within the NuA4 HAT complex to drive H4K12 acetylation and transcription of CSF1, promoting macrophage M2 polarization and immunosuppression in TNBC. ChIP (GRHL2 binding to MORF4L2 enhancer), RNA-seq, Western blot, ELISA, in vitro co-culture, orthotopic TNBC mouse model, CSF1R inhibitor (BLZ549) Biomarker research Medium 39780291
2014 Biallelic GRHL2 mutations (p.Tyr398His and p.Ile482Lys) cause autosomal-recessive ectodermal dysplasia syndrome; the p.Ile482Lys mutation causes altered keratinocyte morphology, impaired tight junctions, adhesion defects, and cytoplasmic mis-localization of GRHL2 protein; transcriptome analysis reveals dysregulation of cell–cell and cell–matrix adhesion gene networks. Whole-exome sequencing, immortalized keratinocyte cell biology (morphology, tight junction assays), immunofluorescence subcellular localization, transcriptome analysis American journal of human genetics Medium 25152456

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification. Scientific reports 127 26887977
2013 Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer. The Journal of biological chemistry 111 23814079
2007 The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment. Human molecular genetics 102 17921507
2015 GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells. The Journal of cell biology 90 26527742
2017 Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer. Cancer research 88 28473532
2012 Grhl2 determines the epithelial phenotype of breast cancers and promotes tumor progression. PloS one 85 23284647
2002 Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28. Human molecular genetics 82 12393799
2017 The GRHL2/ZEB Feedback Loop-A Key Axis in the Regulation of EMT in Breast Cancer. Journal of cellular biochemistry 81 28266048
2018 GRHL2-Dependent Enhancer Switching Maintains a Pluripotent Stem Cell Transcriptional Subnetwork after Exit from Naive Pluripotency. Cell stem cell 78 30017589
2008 Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene 78 19015635
2019 CircTRNC18 inhibits trophoblast cell migration and epithelial-mesenchymal transition by regulating miR-762/Grhl2 pathway in pre-eclampsia. RNA biology 72 31354028
2016 Mesenchymal-Epithelial Transition in Sarcomas Is Controlled by the Combinatorial Expression of MicroRNA 200s and GRHL2. Molecular and cellular biology 72 27402864
2017 Grhl2 reduces invasion and migration through inhibition of TGFβ-induced EMT in gastric cancer. Oncogenesis 70 28067907
2019 The role of GRHL2 and epigenetic remodeling in epithelial-mesenchymal plasticity in ovarian cancer cells. Communications biology 68 31372511
2011 Grhl2 deficiency impairs otic development and hearing ability in a zebrafish model of the progressive dominant hearing loss DFNA28. Human molecular genetics 67 21610158
2012 Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism. Cell death & disease 62 23254293
2015 A Grhl2-dependent gene network controls trophoblast branching morphogenesis. Development (Cambridge, England) 61 25758223
2019 The Lineage Determining Factor GRHL2 Collaborates with FOXA1 to Establish a Targetable Pathway in Endocrine Therapy-Resistant Breast Cancer. Cell reports 56 31644911
2008 Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma. Journal of hepatology 56 18752864
2019 Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2. Journal of dental research 53 31340691
2014 Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome. American journal of human genetics 49 25152456
2020 M2 macrophage-derived extracellular vesicles promote gastric cancer progression via a microRNA-130b-3p/MLL3/GRHL2 signaling cascade. Journal of experimental & clinical cancer research : CR 47 32660626
2018 Ectopic GRHL2 Expression Due to Non-coding Mutations Promotes Cell State Transition and Causes Posterior Polymorphous Corneal Dystrophy 4. American journal of human genetics 47 29499165
2019 Spinal neural tube closure depends on regulation of surface ectoderm identity and biomechanics by Grhl2. Nature communications 46 31171776
2014 Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1. Cancer biology & therapy 46 24756066
2017 Grainyhead-like 2 (GRHL2) regulates epithelial plasticity in pancreatic cancer progression. Cancer medicine 45 28960866
2020 Tumor-derived extracellular vesicles containing microRNA-1290 promote immune escape of cancer cells through the Grhl2/ZEB1/PD-L1 axis in gastric cancer. Translational research : the journal of laboratory and clinical medicine 44 33321257
2011 Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse. Human molecular genetics 43 21262862
2013 Confirmation of GRHL2 as the gene for the DFNA28 locus. American journal of medical genetics. Part A 39 23813623
2013 Bridging cancer biology with the clinic: relative expression of a GRHL2-mediated gene-set pair predicts breast cancer metastasis. PloS one 36 23441166
2020 CircZDHHC20 represses the proliferation, migration and invasion in trophoblast cells by miR-144/GRHL2 axis. Cancer cell international 35 31956297
2015 The p63 Gene Is Regulated by Grainyhead-like 2 (GRHL2) through Reciprocal Feedback and Determines the Epithelial Phenotype in Human Keratinocytes. The Journal of biological chemistry 35 26085095
2016 MiR-217 is down-regulated in psoriasis and promotes keratinocyte differentiation via targeting GRHL2. Biochemical and biophysical research communications 34 26826389
1985 Phase II study of combination bleomycin, vincristine and high-dose methotrexate (BOM) with leucovorin rescue in advanced squamous cell carcinoma of the anal canal. Cancer chemotherapy and pharmacology 33 2414024
2015 Associations of genetic variations in EYA4, GRHL2 and DFNA5 with noise-induced hearing loss in Chinese population: a case- control study. Environmental health : a global access science source 31 26400775
2017 Suppression of the grainyhead transcription factor 2 gene (GRHL2) inhibits the proliferation, migration, invasion and mediates cell cycle arrest of ovarian cancer cells. Cell cycle (Georgetown, Tex.) 30 28278050
2019 GRHL2 inhibits colorectal cancer progression and metastasis via oppressing epithelial-mesenchymal transition. Cancer biology & therapy 28 31063022
2019 VULCAN integrates ChIP-seq with patient-derived co-expression networks to identify GRHL2 as a key co-regulator of ERa at enhancers in breast cancer. Genome biology 28 31084623
2019 The Phosphorylated Estrogen Receptor α (ER) Cistrome Identifies a Subset of Active Enhancers Enriched for Direct ER-DNA Binding and the Transcription Factor GRHL2. Molecular and cellular biology 27 30455249
2018 Grainyhead-like 2 (GRHL2) knockout abolishes oral cancer development through reciprocal regulation of the MAP kinase and TGF-β signaling pathways. Oncogenesis 27 29735981
2017 GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer. American journal of translational research 27 28979695
2022 GRHL2 motif is associated with intratumor heterogeneity of cis-regulatory elements in luminal breast cancer. NPJ breast cancer 25 35676392
2020 GRHL2 induces liver fibrosis and intestinal mucosal barrier dysfunction in non-alcoholic fatty liver disease via microRNA-200 and the MAPK pathway. Journal of cellular and molecular medicine 25 32324317
2020 Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure. Disease models & mechanisms 24 32005677
2017 GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation. Journal of the American Society of Nephrology : JASN 24 29237740
2015 Diverse expression patterns of the EMT suppressor grainyhead-like 2 (GRHL2) in normal and tumour tissues. International journal of cancer 24 26355710
2011 The grainyhead-like 2 gene (GRHL2) single nucleotide polymorphism is not associated with age-related hearing impairment in Han Chinese. The Laryngoscope 22 21557239
2019 Knockdown of GRHL2 inhibited proliferation and induced apoptosis of colorectal cancer by suppressing the PI3K/Akt pathway. Gene 21 30917932
2015 Evaluation of the contribution of the EYA4 and GRHL2 genes in Korean patients with autosomal dominant non-syndromic hearing loss. PloS one 20 25781927
2013 Early detection of bone metabolism changes under different antiepileptic drugs (ED-BoM-AED)--a prospective multicenter study. Epilepsy research 20 23916144
2018 Overexpression of Grainyhead-like 3 causes spina bifida and interacts genetically with mutant alleles of Grhl2 and Vangl2 in mice. Human molecular genetics 19 30189017
2018 Lung morphogenesis is orchestrated through Grainyhead-like 2 (Grhl2) transcriptional programs. Developmental biology 19 30194919
2013 Association between genetic variations in GRHL2 and noise-induced hearing loss in Chinese high intensity noise exposed workers: a case-control analysis. Industrial health 17 24131873
2013 Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis. American journal of physiology. Lung cellular and molecular physiology 17 24375798
2019 Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy. Experimental eye research 16 31233731
2015 Grhl2 is required in nonneural tissues for neural progenitor survival and forebrain development. Genesis (New York, N.Y. : 2000) 16 26177923
2020 GRHL2 Acts as an Anti-Oncogene in Bladder Cancer by Regulating ZEB1 in Epithelial-Mesenchymal Transition (EMT) Process. OncoTargets and therapy 15 32280236
1983 Localization and nucleotide sequence of the bom region of Clo DF13. Molecular & general genetics : MGG 15 6336327
2020 SNAI1-Driven Sequential EMT Changes Attributed by Selective Chromatin Enrichment of RAD21 and GRHL2. Cancers 14 32370157
2016 Genetic Variation in POU4F3 and GRHL2 Associated with Noise-Induced Hearing Loss in Chinese Population: A Case-Control Study. International journal of environmental research and public health 14 27271650
2015 Bom m 9 from Bombyx mori is a novel protein related to asthma. Microbiology and immunology 13 26094648
2022 GRHL2 Enhances Phosphorylated Estrogen Receptor (ER) Chromatin Binding and Regulates ER-Mediated Transcriptional Activation and Repression. Molecular and cellular biology 11 36036613
2019 Interrogating the Grainyhead-like 2 (Grhl2) genomic locus identifies an enhancer element that regulates palatogenesis in mouse. Developmental biology 11 31782997
2018 Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2. Journal of dental research 11 29443638
2023 GRHL2 and AP2a coordinate early surface ectoderm lineage commitment during development. iScience 10 36843855
2024 Blocking lactate regulation of the Grhl2/SLC31A1 axis inhibits trophoblast cuproptosis and preeclampsia development. Journal of assisted reproduction and genetics 9 39287710
2024 GRHL2 regulates keratinocyte EMT-MET dynamics and scar formation during cutaneous wound healing. Cell death & disease 9 39402063
2023 RBM25 induces trophoblast epithelial-mesenchymal transition and preeclampsia disorder by enhancing the positive feedback loop between Grhl2 and RBM25. Experimental biology and medicine (Maywood, N.J.) 9 37728157
2018 Grhl2 regulation of SPINT1 expression controls salivary gland development. Biochemical and biophysical research communications 9 30193734
2016 GRHL2 genetic polymorphisms may confer a protective effect against sudden sensorineural hearing loss. Molecular medicine reports 9 26847018
2024 Identification of lineage-specific epigenetic regulators FOXA1 and GRHL2 through chromatin accessibility profiling in breast cancer cell lines. Cancer gene therapy 8 38429368
2023 GRHL2 Regulation of Growth/Motility Balance in Luminal versus Basal Breast Cancer. International journal of molecular sciences 8 36768838
2022 LncRNA XIST sponges microRNA-448 to promote malignant behaviors of colorectal cancer cells via regulating GRHL2. Functional & integrative genomics 8 35725976
2021 Novel GRHL2 Gene Variant Associated with Hearing Loss: A Case Report and Review of the Literature. Genes 8 33810548
2022 Hypermethylation of the GRHL2 promoter region is associated with ovarian endometriosis. Reproduction (Cambridge, England) 7 35356893
2021 Medication for Acromegaly Reduces Expression of MUC16, MACC1 and GRHL2 in Pituitary Neuroendocrine Tumour Tissue. Frontiers in oncology 7 33680922
2019 Polymorphism in GRHL2 gene may contribute to noise-induced hearing loss susceptibility: a meta-analysis. Brazilian journal of otorhinolaryngology 7 30853467
2008 Autochthonous canine visceral leishmaniasis in a non-endemic area: Bom Sucesso, Minas Gerais State, Brazil. Cadernos de saude publica 7 18278274
2023 A non-coding insertional mutation of Grhl2 causes gene over-expression and multiple structural anomalies including cleft palate, spina bifida and encephalocele. Human molecular genetics 6 37364051
2023 Silencing of GRHL2 induces epithelial‑to‑mesenchymal transition in lung cancer cell lines with different effects on proliferation and clonogenic growth. Oncology letters 6 37600329
2022 Correlation analysis between CD133, Klk3 and grhl2 expression and tumor characteristics in prostate cancer. Cellular and molecular biology (Noisy-le-Grand, France) 6 35818212
2017 Expression and significance of GRHL2 in esophageal cancer. OncoTargets and therapy 6 28435293
2022 Circ_0111277 suppresses trophoblast cell proliferation, angiogenesis, migration, invasion and EMT via regulating miR-188-3p/GRHL2 axis. American journal of reproductive immunology (New York, N.Y. : 1989) 5 36409529
2020 Behavioral effects of benzylideneoxymorphone (BOM), a low efficacy µ opioid receptor agonist and a δ opioid receptor antagonist. Psychopharmacology 5 32820390
2019 Bom-miR-2805 upregulates the expression of Bombyx mori fibroin light chain gene in vivo. Journal of cellular biochemistry 5 31106458
2018 Age-Related Hearing Impairment Associated NAT2, GRM7, GRHL2 Susceptibility Gene Polymorphisms and Haplotypes in Roma and Hungarian Populations. Pathology oncology research : POR 5 29455378
2025 MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer. Biomarker research 4 39780291
2021 Delineating the roles of Grhl2 in craniofacial development through tissue-specific conditional deletion and epistasis approaches in mouse. Developmental dynamics : an official publication of the American Association of Anatomists 4 33638290
2018 CAPA periviscerokinin-mediated activation of MAPK/ERK signaling through Gq-PLC-PKC-dependent cascade and reciprocal ERK activation-dependent internalized kinetics of Bom-CAPA-PVK receptor 2. Insect biochemistry and molecular biology 4 29730398
1993 Purification of aminoacyl-tRNA synthetase kinase activities associated with threonyl- and tyrosyl-tRNA synthetases isolated from Bom:NMRI mouse liver. Biochemistry and molecular biology international 4 8508146
2025 The MLL3/GRHL2 complex regulates malignant transformation and anti-tumor immunity in squamous cancer. The Journal of experimental medicine 3 39964485
2024 An estrogen-regulated long non-coding RNA NCALD promotes luminal breast cancer proliferation by activating GRHL2. Cancer cell international 3 38291441
2024 GRHL2 suppression of NT5E/CD73 in breast cancer cells modulates CD73-mediated adenosine production and T cell recruitment. iScience 3 38706844
1993 Autophosphorylation of degradation products of arginyl-tRNA synthetase protein, isolated from Bom:NMRI mouse liver. Biochemistry and molecular biology international 3 8275013
2025 The activity of the EMT suppressor GRHL2 is regulated by SUMOylation. The Journal of biological chemistry 2 40889682
2024 Elevated GRHL2 Imparts Plasticity in ER-Positive Breast Cancer Cells. Cancers 2 39199676
2022 Abnormal GRHL2 Methylation Confers Malignant Progression to Acute Leukemia. Applied bionics and biomechanics 2 35855840
2015 [Expression and clinical significance of GRHL2 in colorectal cancer]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 2 26813596
2003 Structural plasmid evolution as a result of coupled recombinations at bom and cer sites. Molecular genetics and genomics : MGG 2 14564507
1987 Time development of distribution and toxicity following single toxic APAP doses in male BOM:NMRI mice. Journal of applied toxicology : JAT 2 3611591

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