Affinage

Showing ONECUT1 — HNF6 is a alias.

ONECUT1

Hepatocyte nuclear factor 6 · UniProt Q9UBC0

Length
465 aa
Mass
51.0 kDa
Annotated
2026-06-10
73 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ONECUT1 (HNF-6) is a bipartite cut-homeodomain transcription factor whose single cut domain and homeodomain together recognize DNA, with X-ray crystallography of the domain bound to a transthyretin-promoter site defining the recognition mechanism that underlies its dual mode of activation (PMID:17223534). As a direct activator it binds and stimulates promoters of a hepatic/endoderm transcription-factor network, including HNF-3β, HNF-4, the protein C gene, Glut-2, Pdx1, Ngn3, Hnf1β and CYP7A1 (PMID:9441664, PMID:9441665, PMID:9553065, PMID:11934848, PMID:11915024, PMID:12781686, PMID:15349898, PMID:19766716), positioning it at the apex of cascades that drive biliary tract morphogenesis (an HNF6→HNF1β cascade) and pancreas specification and endocrine differentiation (PMID:11934848, PMID:12781686, PMID:19766716). Its activity is tuned by physical partners: it acts as a coactivator that synergizes with FoxA2 and recruits p300/CBP through an LXXLL motif in the cut domain (PMID:12509444), cooperates with C/EBPα to recruit CBP (PMID:16440369) and Glis3 at the Ngn3 promoter (PMID:22820919), while CUX2, SHP (NR0B2) and elevated FoxA2 antagonize it by competing for or inhibiting DNA binding (PMID:12509444, PMID:18459945, PMID:26218442). Upstream, growth hormone induces hnf6 transcription via STAT5 and HNF-4 at the promoter (PMID:10674400), vHNF1/TCF2 acts through an intronic enhancer (PMID:16380477), and miR-495/miR-218/let-7b repress it post-transcriptionally (PMID:19913497, PMID:23684747); a long-range enhancer ~664 kb away carrying a T2D-associated GATA-disrupting variant is required for its pancreatic expression (PMID:39163202). In adult liver ONECUT1 switches to a repressor of lipogenic genes, facilitating Rev-erbα occupancy, such that its loss causes hepatic steatosis (PMID:27445394). Beyond endoderm it directs retinal horizontal-cell and cone fate downstream of FoxN4/Pax6 and upstream of Lim1/Prox1, acting redundantly with Onecut2 (PMID:23926259, PMID:23867227, PMID:25228773, PMID:25794677), and regulates motor-neuron genes (agrin, neuregulin-2) required for neuromuscular junction formation (PMID:23227180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1997 Medium

    Established the core identity of HNF-6 as a cut-homeodomain DNA-binding transcription factor and placed it upstream of other liver transcription factors, answering what kind of molecule it is and where it sits in a regulatory hierarchy.

    Evidence Yeast one-hybrid cDNA isolation and cotransfection reporter assays on HNF-3β, TTR and HNF-4 promoters in hepatic cells

    PMID:9441664 PMID:9441665

    Open questions at the time
    • Direct in vivo binding to endogenous targets not yet shown
    • No structural basis for DNA recognition
  2. 1998 High

    Demonstrated direct, sequence-specific transcriptional activation by HNF-6 at a defined promoter, converting the inferred activator role into a mutation-validated mechanism.

    Evidence EMSA, site-directed mutagenesis (-14 T→C) and reporter assays on the protein C gene promoter

    PMID:9553065

    Open questions at the time
    • Single target gene
    • No genome-wide binding map
  3. 2000 High

    Defined upstream control of hnf6 by growth hormone and revealed gain-of-function consequences, showing both how the factor is regulated and that its levels must be temporally limited for normal islet function.

    Evidence EMSA and promoter mutagenesis with in vivo GH treatment of hypophysectomized rats; pdx1(PB)-HNF6 transgenic mice with histology and glucose challenge

    PMID:10674400 PMID:10851133

    Open questions at the time
    • Mechanism of timed downregulation in endocrine cells not defined
    • Direct STAT5/HNF-4 cooperativity at the promoter not structurally resolved
  4. 2002 High

    Established in vivo developmental requirement for HNF-6 in biliary morphogenesis via a direct HNF6→HNF1β cascade and confirmed direct Glut-2 activation, linking the factor to organ development and hepatic glucose handling.

    Evidence Hnf6−/− mouse phenotyping with promoter-reporter assays and immunostaining; in vivo adenoviral co-infection and DNA binding for Glut-2

    PMID:11915024 PMID:11934848

    Open questions at the time
    • Full set of biliary effectors downstream of HNF1β not enumerated
    • Intrahepatic vs extrahepatic duct mechanism differences unresolved
  5. 2003 High

    Positioned HNF-6 as a direct upstream timing regulator of pancreas specification and uncovered a partner-based mechanism for tuning its activity through FoxA2 and p300/CBP recruitment.

    Evidence Hnf6−/− embryo analysis with Pdx1 promoter assays; protein-binding, LXXLL mutagenesis, DNA binding and cotransfection for FoxA2 interaction

    PMID:12509444 PMID:12781686

    Open questions at the time
    • Quantitative balance between coactivation and FoxA2-mediated inhibition in vivo unclear
    • Structural detail of the cut-homeodomain/winged-helix interface not resolved
  6. 2004 High

    Expanded the target repertoire (CYP7A1, HNF4α P2 promoter) and revealed indirect regulation via TGF-β suppression, broadening HNF-6 from a simple activator to a network hub with both direct and indirect outputs.

    Evidence Promoter mutagenesis with in vivo adenoviral/GH validation (CYP7A1); double-KO mice and transgenesis (HNF4α P2); Hnf6−/− cells with TGF-β inhibition (Foxa1)

    PMID:15159395 PMID:15349898 PMID:15562441

    Open questions at the time
    • Direct vs indirect contributions to bile acid homeostasis not separated
    • Mechanism linking HNF-6 loss to TGF-βRII upregulation unknown
  7. 2006 High

    Defined a C/EBPα–HNF-6–CBP coactivation complex confirmed in vivo and showed vHNF1/TCF2 acts through an intronic enhancer upstream of HNF6, mapping both protein-complex and cis-regulatory inputs.

    Evidence Cotransfection, reciprocal co-IP from liver extracts and ChIP for C/EBPα; EMSA, footprinting, endoderm electroporation, transgenesis and gene inactivation for vHNF1

    PMID:16380477 PMID:16440369

    Open questions at the time
    • Stoichiometry and structure of the HNF-6/C/EBPα/CBP complex unknown
    • Other inputs into the intronic enhancer not characterized
  8. 2007 High

    Resolved the crystal structure of the bipartite cut-homeodomain bound to DNA, providing the structural basis for sequence recognition and context-dependent dual activation.

    Evidence X-ray crystallography of the HNF-6α cut+homeodomain complexed with the TTR promoter site; double-KO mouse analysis of hepatoblast migration

    PMID:17223534 PMID:17936262

    Open questions at the time
    • Structure of full-length protein with coactivators not solved
    • Basal-lamina degradation effectors only partly mapped
  9. 2008 High

    Identified SHP (NR0B2) as a repressor that inhibits HNF-6 DNA binding, adding a nuclear-receptor brake on gluconeogenic target genes G6Pase and PEPCK.

    Evidence Cotransfection, protein-binding, EMSA, ChIP, confocal microscopy and adenoviral SHP/siRNA experiments

    PMID:18459945

    Open questions at the time
    • Physiological conditions triggering SHP-mediated repression not defined
  10. 2009 High

    Established HNF6 as a direct activator of the pro-endocrine gene Ngn3 required for progenitor entry into the endocrine lineage, and identified miRNA control of its mRNA.

    Evidence Conditional Cre-lox inactivation and Ngn3 promoter assays; miR-495/miR-218 3'UTR reporter and endogenous mRNA quantification

    PMID:19766716 PMID:19913497

    Open questions at the time
    • In vivo relevance of miR-495/miR-218 regulation not tested
    • Co-factor requirements at the Ngn3 promoter not yet defined
  11. 2012 High

    Linked HNF6 to acinar-to-ductal metaplasia and identified Glis3 as a cooperative partner at Ngn3, refining how HNF6 toggles between acinar repression and ductal/endocrine programs.

    Evidence Gain/loss-of-function in cells and mouse ADM models with human tissue staining; ChIP, luciferase, co-IP and in vitro binding for Glis3; NMJ analysis in Hnf6 mutant mice with co-culture rescue

    PMID:22271799 PMID:22820919 PMID:23227180

    Open questions at the time
    • Direct vs indirect acinar gene repression targets not all defined
    • Mechanism of motor-neuron target selection unclear
  12. 2013 High

    Defined ONECUT1's role in retinal fate determination (horizontal and cone cells, suppression of rod fate) and demonstrated miRNA-enforced repression maintains acinar identity, with HNF6 induction sufficient to derail it.

    Evidence Retina-specific KO, in utero/retinal electroporation and ThrbCRM1 cis-regulatory analysis; pancreas/acinar Dicer KO, Dicer/Hnf6 double-KO epistasis and miRNA modulation

    PMID:23684747 PMID:23867227 PMID:23926259

    Open questions at the time
    • Combinatorial logic with Otx2/Ptf1a at cis-regulatory modules incompletely mapped
    • In vivo miRNA contribution to acinar identity quantitatively unresolved
  13. 2014 High

    Demonstrated functional redundancy with Onecut2 in retina, showing the two factors jointly confer progenitor competence for early cell fates and suppress rod fate.

    Evidence Oc1/Oc2 double-knockout mice with RNA-Seq target identification and cell-type quantification

    PMID:25228773

    Open questions at the time
    • Direct vs indirect status of RNA-Seq targets not fully resolved
  14. 2015 High

    Mapped the genome-wide HNF6 cistrome (~40,000 sites) and revealed CUX2 competition at shared sex-specific gene loci, plus Pax6-dependent maintenance of Onecut expression in horizontal cells.

    Evidence ChIP-seq cistrome mapping, EMSA competition and reporter assays (CUX2); single/compound Onecut and Pax6 KO with marker immunostaining

    PMID:25794677 PMID:26218442

    Open questions at the time
    • Determinants of activator vs repressor outcome at cistrome-wide sites not defined
    • How Pax6 maintains Onecut expression mechanistically unknown
  15. 2016 High

    Revealed HNF6's adult-liver function as a repressor of lipogenic genes that facilitates Rev-erbα occupancy, and as a GH-dependent anti-apoptotic factor acting through direct target Ciap1.

    Evidence Adult liver-specific deletion with RNA-seq and ChIP-seq for HNF6/Rev-erbα; Hnf6 conditional KO with bile duct ligation, ChIP-on-chip and EMSA for Ciap1

    PMID:27445394 PMID:27936029

    Open questions at the time
    • Molecular switch between activator and repressor modes in liver not defined
    • Direct interaction with Rev-erbα not established
  16. 2019 High

    Genome-wide direct target mapping in embryonic pancreas established ONECUT1 as a direct regulator of both acinar and ductal gene programs, anchoring its exocrine differentiation role.

    Evidence ChIP-seq direct target identification, RNA-seq on Oc1-deficient pancreas and immunofluorescence validation

    PMID:30831323

    Open questions at the time
    • Logic determining acinar vs ductal target output not resolved
  17. 2021 High

    Human pluripotent stem cell models established ONECUT1 as a regulator of transcriptional and epigenetic machinery preparing pancreatic progenitors for endocrine specification, translating mouse findings to human development.

    Evidence hPSC directed differentiation with loss-of-function, ChIP-seq, ATAC-seq and RNA-seq across stages

    PMID:34663987 PMID:34789845

    Open questions at the time
    • Direct vs indirect control of enhancer accessibility not separated
    • Causal chain to NKX2.2/NKX6.1 not fully mapped
  18. 2024 High

    Identified a required long-range enhancer ~664 kb upstream and a T2D-associated variant disrupting GATA binding, connecting ONECUT1 cis-regulation to disease risk.

    Evidence CRISPRi screen in hPSC pancreatic differentiation, homozygous enhancer deletion and ChIP for GATA4/GATA6/FOXA2 at the risk variant

    PMID:39163202

    Open questions at the time
    • Population-level penetrance of the variant not addressed
    • 3D chromatin contact between enhancer and promoter not directly demonstrated
  19. 2025 Medium

    Extended ONECUT1 into cancer contexts as a regulator of metabolism and immune evasion, acting as a PSAT1 activator in lung squamous carcinoma and a tumor suppressor downstream of β-Catenin in hepatoblastoma.

    Evidence ChIP and luciferase assays with overexpression/knockdown and co-culture in LUSC cells; inducible transposon murine hepatoblastoma model with transcriptomics and T cell depletion

    PMID:39999468 PMID:40907151

    Open questions at the time
    • Single cancer cell line for PSAT1 mechanism
    • Whether tumor-suppressive effect is cell-autonomous vs immune-mediated not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular switch that determines whether ONECUT1 acts as an activator or repressor at a given genomic site, and how its cofactor and chromatin context dictate context-specific outputs across endoderm, retina, motor neurons and tumors, remains unresolved.
  • No structural model of activator vs repressor cofactor complexes
  • Determinants of tissue-specific target selection not defined
  • Mechanistic basis for Rev-erbα facilitation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2
Partners
CEBPACREBBPCUX2EP300FOXA2GLIS3NR0B2NR1D1

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 HNF-6 encodes a cut-homeodomain-containing transcription factor that directly binds DNA and activates expression of reporter genes driven by HNF-6 binding sites from the HNF-3β and transthyretin (TTR) promoter regions, establishing HNF-3β as a transcriptional target of HNF-6. Yeast one-hybrid system (cDNA isolation), cotransfection reporter assays Developmental biology Medium 9441664
1997 HNF-6 transcriptionally stimulates the HNF-4 and HNF-3β promoters, placing HNF-6 upstream of these factors in a liver transcription factor regulatory network. Transfection/reporter assays in hepatic cells Developmental biology Medium 9441665
1998 HNF-6 and HNF-1 bind the protein C gene promoter in a mutually exclusive manner; a -14 T→C mutation reduces HNF-6 binding and abolishes HNF-6-mediated transactivation, demonstrating HNF-6 is a direct transcriptional activator of the protein C gene. DNA binding (EMSA), transient transfection/reporter assays, site-directed mutagenesis The Journal of biological chemistry High 9553065
2000 GH stimulates transcription of the hnf6 gene via a mechanism requiring STAT5 binding (~-110 bp) and HNF-4 binding (~-650 bp) in the hnf6 promoter; both STAT5 binding and HNF-4 binding affinity are increased in liver within 1 h of GH injection. DNA binding assays (EMSA), transfection with site-directed mutagenesis of promoter-reporter constructs, in vivo GH treatment of hypophysectomized rats Molecular endocrinology High 10674400
2000 Persistent HNF-6 expression in pancreatic endocrine cells (beyond E18.5) via pdx1(PB) transgene causes disrupted islet architecture, loss of GLUT2 expression in beta cells, and diabetes, demonstrating that timely downregulation of HNF-6 in endocrine cells is required for normal islet organization and beta cell function. Transgenesis (pdx1(PB)-HNF6 mice), histology, marker analysis, glucose challenge Development High 10851133
2002 HNF-6 is required for normal development of the biliary tract: Hnf6−/− mice lack a gallbladder, show abnormal extrahepatic bile ducts, and have perturbed intrahepatic bile duct development. HNF-6 directly stimulates the Hnf1β promoter, and HNF1β expression is downregulated in Hnf6−/− intrahepatic bile ducts, establishing a HNF6→HNF1β regulatory cascade in biliary development. Hnf6−/− mouse phenotype analysis, promoter-reporter assays (HNF-6 stimulation of Hnf1β promoter), immunostaining Development High 11934848
2002 HNF-6 directly activates the Glut-2 promoter via sequences at -185 to -144 bp; only HNF-6 (not HNF-3 proteins) binds this region and provides transcriptional activation, and maintaining HNF-6 during AdHNF3β infection restores hepatic Glut-2 levels and glycogen. In vivo adenoviral co-infection, DNA binding assays, cotransfection assays in HepG2 cells Hepatology High 11915024
2003 HNF-6 controls timing of pancreas specification upstream of Pdx-1: onset of Pdx-1 expression is delayed in Hnf6−/− embryos in both ventral and dorsal endoderm, and HNF-6 directly stimulates the Pdx1 promoter in transfection assays. Hnf6−/− mouse phenotype analysis, promoter-reporter (cotransfection) assays Developmental biology High 12781686
2003 HNF-6 physically interacts with FoxA2 through the HNF-6 Cut-Homeodomain and FoxA2 winged-helix DNA binding domains; HNF-6 acts as a coactivator to synergistically stimulate FoxA2 transcriptional activity by recruiting p300/CBP coactivators via an LXXLL sequence in the Cut domain. Conversely, increased FoxA2 levels inhibit HNF-6 DNA binding at HNF-6-specific sites, repressing HNF-6 activation of the Glut-2 promoter. HepG2 cotransfection assays, protein-binding assays, site-directed mutagenesis of LXXLL, DNA binding assays Molecular and cellular biology High 12509444
2004 HNF-6 directly activates the CYP7A1 promoter through sequences at -206/-194 bp as demonstrated by deletional and mutational analyses; increasing HNF-6 levels in vivo (by adenovirus or GH treatment) induces CYP7A1 mRNA, linking HNF-6 to bile acid homeostasis. Cotransfection with deletional/mutational promoter analysis, in vivo adenoviral infection, GH treatment model Hepatology High 15349898
2004 HNF6/OC-2 and HNF1 binding sites in the HNF4α P2 promoter are functional; HNF6/OC-2 double-deficient embryos show reduced HNF4α7 transcript levels, and HNF4α1 represses P2 activity, establishing a developmental switch from HNF6/OC-2-driven P2 to HNF4α1-driven P1 promoter activity. Site-directed mutagenesis of P2 promoter, double-KO mouse analysis, transient transgenesis, transfection assays, quantitative PCR The Journal of biological chemistry High 15159395
2004 HNF-6 indirectly inhibits Foxa1 expression by suppressing TGF-β signaling: in Hnf6−/− liver/cells, TGF-β receptor II is upregulated, leading to increased TGF-β signaling that drives Foxa1 expression. Inhibition of TGF-β signaling in Hnf6−/− cells down-regulates Foxa1. Hnf6−/− mouse analysis, BMEL cell lines, TGF-β signaling inhibition experiments Hepatology Medium 15562441
2006 C/EBPα forms a protein complex with HNF-6 requiring the HNF-6 cut domain and C/EBPα AD1/AD2 sequences; this complex stimulates HNF-6-dependent transcription by recruiting the CBP coactivator. Co-immunoprecipitation from liver extracts confirms the in vivo association between HNF-6, C/EBPα, and CBP. ChIP assays show that increased C/EBPα and HNF-6 are required for association with the endogenous Foxa2 promoter. HepG2 cotransfection assays, protein-binding assays, co-immunoprecipitation from liver extracts, chromatin immunoprecipitation (ChIP), adenovirus E1A inhibition Hepatology High 16440369
2006 vHNF1/TCF2 acts upstream of HNF6 in the embryonic endoderm via a functional binding site in an intronic enhancer of the Hnf6 gene; loss of vHNF1 reduces HNF6 expression, establishing a vHNF1→HNF6→Pdx1 cascade controlling pancreatic precursor cell generation. In vitro and in vivo protein-DNA interaction (EMSA, footprinting), endoderm electroporation, transgenesis, gene inactivation in embryos Diabetes High 16380477
2007 Crystal structure of the bipartite DNA-binding domain (single cut domain + homeodomain) of HNF-6α complexed with its binding site from the TTR promoter reveals the DNA recognition mechanism and structural basis for the dual mode of transcriptional activation dependent on target gene context. X-ray crystallography (crystal structure determination) Structure High 17223534
2007 HNF-6/OC-1 and OC-2 redundantly stimulate degradation of the basal lamina surrounding the liver bud and promote hepatoblast migration into the septum transversum, operating in a gene network with E-cadherin, thrombospondin-4, and osteopontin. Double-knockout mouse analysis, gene expression analysis Developmental biology Medium 17936262
2008 SHP (NR0B2) physically interacts with HNF-6 in vitro, co-localizes with HNF-6 in the nucleus, and represses HNF-6 transcriptional activity by inhibiting HNF-6 DNA binding at HNF-6-response elements; SHP represses HNF-6 target genes G6Pase and PEPCK in cells. Cotransfection assays, protein-protein binding assays, EMSA, ChIP, confocal microscopy, adenoviral SHP and SHP siRNA experiments The Biochemical journal High 18459945
2009 HNF6 directly activates the Ngn3 (pro-endocrine) gene promoter in the developing pancreas; conditional inactivation of HNF6 from Ngn3-expressing cells reduces multipotent progenitor cells entering the endocrine lineage, establishing HNF6 as a direct upstream activator of Ngn3. Conditional gene inactivation (Cre-lox), reporter/promoter assays Mechanisms of development High 19766716
2009 miR-495 and miR-218 post-transcriptionally repress HNF-6 and OC-2 respectively by targeting their 3'UTRs; overexpression of these miRNAs in cultured cells decreases endogenous HNF-6 and OC-2 mRNA levels. Transient transfection with miRNA mimics, 3'UTR reporter assays, endogenous mRNA quantification Biochemical and biophysical research communications Medium 19913497
2012 HNF6 and Sox9 are ectopically induced in acinar cells during acinar-to-ductal metaplasia (ADM); HNF6 is required for repression of acinar genes, modulation of ADM-associated cell polarity changes, and activation of ductal genes in metaplastic acinar cells, as shown by gain- and loss-of-function experiments. Immunostaining in human and mouse pancreas, gain- and loss-of-function experiments in cultured cells and mouse ADM models Gut High 22271799
2012 Glis3 directly binds the Ngn3 promoter and interacts physically with HNF6 in vitro and in vivo; the amino-terminus of Glis3 and the homeodomain of HNF6 are critical for this interaction, suggesting cooperative regulation of Ngn3 expression. Chromatin immunoprecipitation (binding to Ngn3 promoter), luciferase reporter assay, co-immunoprecipitation, in vitro protein interaction assays Molecules and cells Medium 22820919
2012 HNF-6 regulates in spinal motor neurons the expression of agrin, neuregulin-2, and TGF-β receptor II, which are required for neuromuscular junction formation; Hnf6 mutant mice have abnormal NMJ morphology and defective synaptophysin localization, and defects in NMJ-like co-culture structures are rescued by recombinant agrin and neuregulin. Hnf6 mutant mouse analysis (histology, behavioral tests), gene expression analysis, spinal cord slice/myotube co-culture with recombinant factor rescue PloS one High 23227180
2013 Onecut1 (Oc1) is required for horizontal cell (HC) genesis in the retina: ~80% of HCs fail to form in retina-specific Oc1 KO mice. Epistasis analysis places Oc1 downstream of FoxN4, in parallel with Ptf1a, and upstream of Lim1 and Prox1. Oc1 and Ptf1a together are sufficient (in utero electroporation) to determine HC fate. Retina-specific Oc1 knockout, in utero electroporation for gain-of-function, genetic epistasis analysis with multiple TF mutants The Journal of neuroscience High 23926259
2013 Onecut1 is sufficient to induce cells with earliest markers of cones and horizontal cells; interference with Onecut1 transcriptional activity leads to precocious rod development. A cis-regulatory module (ThrbCRM1) for the Thrb gene is combinatorially regulated by Otx2 and Onecut1, placing Onecut1 in control of cone vs. rod photoreceptor fate. Retinal electroporation for gain- and dominant-negative loss-of-function, cis-regulatory element analysis Developmental cell High 23867227
2013 Let-7b and miR-495 repress HNF6 in pancreatic acinar cells; inhibition of these miRNAs (or Dicer inactivation) leads to HNF6 induction, repression of acinar differentiation, and induction of hepatic genes. Overexpression of HNF6 alone in developing acinar cells is sufficient to repress acinar differentiation. The Dicer-deficient acinar phenotype depends on HNF6 induction (epistasis in Dicer/Hnf6 double-KO). Pancreas/acinar-specific Dicer KO mice, Dicer/Hnf6 double-KO epistasis, miRNA mimic/inhibitor transfection in acinar cells Gastroenterology High 23684747
2014 Onecut1 and Onecut2 act redundantly in retinal development: double-null mice show complete absence of HCs, reduced RGC production, failed starburst amacrine cell genesis, and compromised cone generation. RNA-Seq identified downstream targets, confirming redundancy and showing that onecut factors suppress rod fate, contributing to retinal progenitor competence for early cell fates. Oc1/Oc2 double-knockout mice, RNA-Seq expression profiling, retinal cell type quantification Proceedings of the National Academy of Sciences High 25228773
2015 CUX2 competes with HNF6 for DNA binding at shared genomic binding sites in liver chromatin; in cell-based assays, CUX2 inhibits HNF6 transcriptional regulation of sex-specific gene promoters (CYP2C11, CYP2C12). ChIP-seq identified ~40,000 HNF6-binding sites in mouse liver, with ~90% of CUX2 binding sites co-occupied by HNF6. Cell-based transfection reporter assays, in vitro EMSA, ChIP-seq (HNF6 cistrome mapping) Molecular endocrinology High 26218442
2015 Onecut1 and Onecut2 operate downstream of Pax6 in retinal development to maintain horizontal cells; in Pax6-deficient retinas, Onecut1/2 expression is lost, and compound Onecut1/2 mutants show complete loss of HCs. Genes for HC development (Foxn4, Ptf1a, Prox1, Lim1) show that HCs are initially formed but not maintained in Onecut-deficient retinas. Single and compound Onecut1/Onecut2 KO mouse analysis, Pax6 conditional KO, immunostaining for HC markers and TF expression Developmental biology High 25794677
2016 HNF6 acts as a transcriptional repressor of lipogenic genes in adult liver: liver-specific deletion of HNF6 causes hepatic steatosis, upregulates lipogenic genes directly bound by HNF6, and reduces binding of the circadian nuclear receptor Rev-erbα at these sites, revealing a novel mechanism by which HNF6 represses lipid metabolism genes and facilitates Rev-erbα occupancy. Adult liver-specific HNF6 deletion (Cre-lox), RNA-seq/gene expression, ChIP-seq for HNF6 and Rev-erbα binding Genes & development High 27445394
2016 GH mediates its hepatoprotective effect against apoptosis through HNF6; GH-mediated suppression of caspase-3/-8/-9 and hepatic apoptosis during bile duct ligation is abrogated in Hnf6 conditional KO mice. ChIP and EMSA identified Ciap1 (Birc2) as a direct HNF6 target gene mediating this anti-apoptotic effect. Hnf6 conditional KO mouse model, bile duct ligation, primary hepatocyte cultures, ChIP-on-chip and EMSA PloS one High 27936029
2019 Oc1 (HNF6) is a direct transcriptional regulator of pancreatic exocrine (acinar) differentiation: ChIP-seq in embryonic pancreas identified ~1000 direct Oc1 target genes including acinar regulatory factors (Nr5a2, Ptf1a, Gata4, Mist1) and functional genes (Amylase, Cpa1, Prss1, Spink1), as well as ductal factors Hnf1β and FoxA2. ChIP-seq (direct target identification), RNA-seq on Oc1-deficient pancreas, immunofluorescence validation Cellular and molecular gastroenterology and hepatology High 30831323
2021 Loss of ONECUT1 in human pluripotent stem cell differentiation impairs pancreatic progenitor formation and endocrine program. ONECUT1 loss alters transcription factor binding, enhancer activity, and NKX2.2/NKX6.1 expression in pancreatic progenitors, establishing ONECUT1 as a regulator of transcriptional and epigenetic machinery in endocrine development. hPSC directed differentiation with ONECUT1 loss-of-function, ChIP-seq, ATAC-seq, RNA-seq Nature medicine High 34663987
2021 Stage-specific RNA-seq, ChIP-seq, and ATAC-seq during hPSC pancreatic differentiation identify ONECUT1 as a crucial fate regulator in pancreas progenitors that prepares progenitors for later endocrine specification, acting within a transcriptional and epigenetic regulatory circuitry. RNA-seq, ChIP-seq, ATAC-seq during hPSC pancreatic differentiation Communications biology High 34789845
2024 A long-range enhancer ~664 kb from the ONECUT1 promoter (ONECUT1e-664kb) is required for ONECUT1 expression during pancreatic differentiation; homozygous deletion of this enhancer in hPSCs causes near-complete loss of ONECUT1 expression and impaired pancreatic differentiation. A T2D-associated variant (rs528350911) in this enhancer disrupts a GATA motif and reduces binding of GATA4, GATA6, and FOXA2. CRISPRi screen in hPSC pancreatic differentiation, homozygous enhancer deletion, ChIP for TF binding at risk variant, hPSC differentiation assays Cell reports High 39163202
2025 ONECUT1 transcriptionally activates PSAT1 by directly binding to the PSAT1 promoter, as confirmed by ChIP and dual luciferase assays; ONECUT1 overexpression in lung squamous cell carcinoma cells restores PSAT1-mediated upregulation of PD-L1 expression and immune evasion. ChIP assay, dual luciferase reporter assay, overexpression/knockdown experiments, flow cytometry, co-culture assays Tissue & cell Medium 40907151
2025 ONECUT1 functions as a tumor suppressor downstream of activated β-Catenin in hepatoblastoma; β-Catenin activation suppresses ONECUT1 expression, and co-expression of ONECUT1 with YAP/β-Catenin strongly suppresses hepatoblastoma formation. ONECUT1 negatively regulates tumor cell glycolysis and reshapes the tumor immune microenvironment. Inducible transposon-based murine HB model, doxycycline-inducible ONECUT1 expression, transcriptomic analysis, T cell depletion experiments Hepatology Medium 39999468

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development (Cambridge, England) 288 11934848
2003 The Onecut transcription factor HNF-6 (OC-1) is required for timely specification of the pancreas and acts upstream of Pdx-1 in the specification cascade. Developmental biology 156 12781686
1997 The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. Developmental biology 150 9441664
1997 HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Developmental biology 129 9441665
2003 Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Human molecular genetics 123 14570708
2014 Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development. Proceedings of the National Academy of Sciences of the United States of America 121 25228773
2013 Otx2 and Onecut1 promote the fates of cone photoreceptors and horizontal cells and repress rod photoreceptors. Developmental cell 117 23867227
2012 Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut 103 22271799
2007 The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Developmental biology 100 17936262
2000 Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone. Molecular endocrinology (Baltimore, Md.) 97 10674400
2009 Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation. Mechanisms of development 88 19766716
2000 Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function. Development (Cambridge, England) 77 10851133
2006 Suppression of C/EBPalpha expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development (Cambridge, England) 75 17021047
2006 A vHNF1/TCF2-HNF6 cascade regulates the transcription factor network that controls generation of pancreatic precursor cells. Diabetes 74 16380477
2003 Association between hepatocyte nuclear factor 6 (HNF-6) and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding. Molecular and cellular biology 68 12509444
2004 Expression of the alpha7 isoform of hepatocyte nuclear factor (HNF) 4 is activated by HNF6/OC-2 and HNF1 and repressed by HNF4alpha1 in the liver. The Journal of biological chemistry 66 15159395
2004 The zebrafish onecut gene hnf-6 functions in an evolutionarily conserved genetic pathway that regulates vertebrate biliary development. Developmental biology 66 15385156
2013 Onecut1 is essential for horizontal cell genesis and retinal integrity. The Journal of neuroscience : the official journal of the Society for Neuroscience 61 23926259
2009 Dynamic expression of the Onecut transcription factors HNF-6, OC-2 and OC-3 during spinal motor neuron development. Neuroscience 59 19800948
2016 HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes & development 58 27445394
2014 Up regulation of liver-enriched transcription factors HNF4a and HNF6 and liver-specific microRNA (miR-122) by inhibition of let-7b in mesenchymal stem cells. Chemical biology & drug design 55 25059576
2005 Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6. Development (Cambridge, England) 50 16284120
2004 Pattern of genes influenced by conditional expression of the transcription factors HNF6, HNF4alpha and HNF1beta in a pancreatic beta-cell line. Nucleic acids research 46 15520459
2021 Mutations and variants of ONECUT1 in diabetes. Nature medicine 43 34663987
2004 Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3alpha/Foxa1 gene by TGF-beta in mouse liver. Hepatology (Baltimore, Md.) 42 15562441
2015 Onecut1 and Onecut2 transcription factors operate downstream of Pax6 to regulate horizontal cell development. Developmental biology 36 25794677
2009 MiR-495 and miR-218 regulate the expression of the Onecut transcription factors HNF-6 and OC-2. Biochemical and biophysical research communications 36 19913497
2007 DNA recognition mechanism of the ONECUT homeodomain of transcription factor HNF-6. Structure (London, England : 1993) 36 17223534
2015 Cross Talk Between GH-Regulated Transcription Factors HNF6 and CUX2 in Adult Mouse Liver. Molecular endocrinology (Baltimore, Md.) 34 26218442
2014 Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. The American journal of pathology 34 24631193
2012 Glis3 regulates neurogenin 3 expression in pancreatic β-cells and interacts with its activator, Hnf6. Molecules and cells 33 22820919
2007 The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 17283222
2006 C/EBPalpha and HNF6 protein complex formation stimulates HNF6-dependent transcription by CBP coactivator recruitment in HepG2 cells. Hepatology (Baltimore, Md.) 33 16440369
2014 Sex-dependent regulation of hepatic CYP3A by growth hormone: Roles of HNF6, C/EBPα, and RXRα. Biochemical pharmacology 31 25451687
2013 Let-7b and miR-495 stimulate differentiation and prevent metaplasia of pancreatic acinar cells by repressing HNF6. Gastroenterology 31 23684747
2002 Maintaining HNF6 expression prevents AdHNF3beta-mediated decrease in hepatic levels of Glut-2 and glycogen. Hepatology (Baltimore, Md.) 31 11915024
2021 Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Communications biology 28 34789845
1998 Type I protein C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein C gene promoter. The Journal of biological chemistry 27 9553065
2012 The Onecut transcription factor HNF-6 regulates in motor neurons the formation of the neuromuscular junctions. PloS one 26 23227180
2008 Orphan nuclear receptor SHP interacts with and represses hepatocyte nuclear factor-6 (HNF-6) transactivation. The Biochemical journal 26 18459945
2004 In vivo regulation of murine CYP7A1 by HNF-6: a novel mechanism for diminished CYP7A1 expression in biliary obstruction. Hepatology (Baltimore, Md.) 26 15349898
2008 Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice. American journal of physiology. Gastrointestinal and liver physiology 23 18511741
2004 The role of pdx1 and HNF6 in proliferation and differentiation of endocrine precursors. Diabetes/metabolism research and reviews 23 15037986
2002 Diminished hepatic expression of the HNF-6 transcription factor during bile duct obstruction. Hepatology (Baltimore, Md.) 22 12029624
2018 Identification and characterization of early photoreceptor cis-regulatory elements and their relation to Onecut1. Neural development 20 30466480
2014 Loss of HNF6 expression correlates with human pancreatic cancer progression. Laboratory investigation; a journal of technical methods and pathology 20 24638272
2014 Onecut1 and Onecut2 play critical roles in the development of the mouse retina. PloS one 20 25313862
2010 Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells. PloS one 20 20967225
2008 Loss of ONECUT1 expression in human pancreatic cancer cells. Oncology reports 20 18097590
2003 HNF-6-independent differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia 20 12687336
2013 The Onecut transcription factor HNF-6 contributes to proper reorganization of Purkinje cells during postnatal cerebellum development. Molecular and cellular neurosciences 17 23669529
2019 Regulation of the Pancreatic Exocrine Differentiation Program and Morphogenesis by Onecut 1/Hnf6. Cellular and molecular gastroenterology and hepatology 16 30831323
2018 HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model. Journal of cellular physiology 14 30256389
2000 Variability of the insulin receptor substrate-1, hepatocyte nuclear factor-1alpha (HNF-1alpha), HNF-4alpha, and HNF-6 genes and size at birth in a population-based sample of young Danish subjects. The Journal of clinical endocrinology and metabolism 13 10946909
2023 The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus. Diabetes 12 37639628
2020 Cis-regulatory analysis of Onecut1 expression in fate-restricted retinal progenitor cells. Neural development 12 32192535
2024 CRISPR screening uncovers a long-range enhancer for ONECUT1 in pancreatic differentiation and links a diabetes risk variant. Cell reports 9 39163202
2016 Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6. PloS one 8 27936029
2020 Epigenetic modifications in the GH-dependent Prlr, Hnf6, Cyp7b1, Adh1 and Cyp2a4 genes. Journal of molecular endocrinology 7 31990658
2009 Expression of Xenopus tropicalis HNF6/Onecut-1. The International journal of developmental biology 7 19123138
2001 Mutation screening of the hepatocyte nuclear factor (HNF)-6 gene in Japanese subjects with diabetes mellitus. Diabetes research and clinical practice 6 11323086
2024 HNF6 and HNF4α expression in adenocarcinomas of the liver, pancreaticobiliary tract, and gastrointestinal tract: an immunohistochemical study of 480 adenocarcinomas of the digestive system. Pathology 5 38926048
1999 Type-I protein-C deficiency caused by disruption of a hepatocyte nuclear factor (HNF)-6/HNF-1 binding site in the human protein-C gene promoter. Trends in cardiovascular medicine 5 10578522
2025 β-Catenin regulates distinct pathways from YAP and suppresses ONECUT1 to drive hepatoblastoma development in mice and humans. Hepatology (Baltimore, Md.) 3 39999468
2024 A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes. Cell reports 3 39427318
2015 Transcriptomic analyses of Onecut1 and Onecut2 deficient retinas. Genomics data 2 26484186
2025 Role of HNF6 in liver homeostasis and pathophysiology. Molecular medicine (Cambridge, Mass.) 1 39910442
2025 ONECUT1 activates PSAT1 to facilitate PD-L1 expression and mediate immune evasion of lung squamous cell carcinoma. Tissue & cell 1 40907151
2023 ONECUT1 variants beyond type 1 and type 2 diabetes: exploring clinical diversity and epigenetic associations in Arab cohorts. Frontiers in genetics 1 37941991
2005 [Expression of HNF4alpha and HNF6 mRNA during the process of mouse liver development]. Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition 1 16078569
2026 Overexpression of ONECUT1 suppresses hepatoblastoma progression via modulating tumor cell growth and tumor microenvironment. Cell & bioscience 0 41937186
2024 CRISPR Screening Uncovers a Long-Range Enhancer for ONECUT1 in Pancreatic Differentiation and Links a Diabetes Risk Variant. bioRxiv : the preprint server for biology 0 38746154
2024 CUTting through the distance: A disease-relevant long-range ONECUT1 enhancer. Cell reports 0 39427317

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