Affinage

HNF1A

Hepatocyte nuclear factor 1-alpha · UniProt P20823

Length
631 aa
Mass
67.4 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HNF1A (LFB1/HNF1α) is a tissue-restricted homeodomain transcription factor that drives differentiated gene programs in liver, kidney, intestine, and the endocrine pancreas (PMID:2357969, PMID:8417340). It recognizes the inverted palindrome GTTAATNATTAAC through a tripartite DNA-binding module — an N-terminal dimerization domain, a POU-A-related region, and an atypical extended homeodomain carrying a 21-residue insertion that lengthens helix 2 but does not contact DNA — and binds either as a homodimer or as a heterodimer with the related factor vHNF1 (HNF1B/LFB3) (PMID:1356766, PMID:8491173, PMID:9126845). DNA binding and dimer stability are enhanced by the cofactor DCoH, which forms heterotetramers with HNF1A dimers, promotes binding to suboptimal sites, and abolishes HNF1A-RNA interactions while retaining its own pterin-4α-carbinolamine dehydratase activity (PMID:8995521), and transactivation is further potentiated by Mirk/Dyrk1B-mediated phosphorylation bridged through a DCoH family member (PMID:11980910). HNF1A activates an extensive battery of metabolic and transport genes — including glucokinase, GLUT2/SGLT1 glucose transporters, PCSK9, and insulin — thereby coupling its transcriptional output to beta-cell glucose sensing, hepatic cholesterol handling, and epithelial transport (PMID:11460882, PMID:32711050, PMID:34035238, PMID:28204827, PMID:26808453). Its own expression sits within a regulatory hierarchy: HNF4 acts upstream and is required for proper activation, HNF1A negatively autoregulates its promoter, and the HASTER cis-regulatory locus enforces cell-specific HNF1A concentrations through feedback that prevents binding to inappropriate genomic regions (PMID:8808405, PMID:7937157, PMID:36202974). Loss of this control underlies maturity-onset diabetes of the young type 3 (MODY3): pathogenic mutations reduce transcriptional activity and nuclear localization, act as dominant-negatives, or trigger nonsense-mediated decay producing haploinsufficiency, ultimately disrupting beta-cell metabolic coupling and insulin secretion (PMID:26853433, PMID:10944108, PMID:31145732, PMID:34035238, PMID:36563694).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1990 High

    Establishing that HNF1A is controlled at the transcriptional level and is the determinant of the hepatic differentiated state addressed how a tissue-specific factor is itself switched on and off.

    Evidence Nuclear run-on transcription assays and Northern blotting across dedifferentiated hepatoma variants, somatic hybrids, and revertants

    PMID:2357969

    Open questions at the time
    • Upstream transcriptional inputs not yet identified
    • Does not define HNF1A target genes
  2. 1991 High

    Demonstrating that HNF1A heterodimerizes with vHNF1 and that vHNF1 can transactivate target promoters defined a combinatorial code for HNF1-family transcriptional output.

    Evidence In vitro dimerization assays, co-immunoprecipitation from kidney/liver nuclear extracts, transfection reporter assays on the albumin promoter

    PMID:1673925 PMID:1673926

    Open questions at the time
    • Functional consequence of homo- vs heterodimer choice on target selection unresolved
    • Cofactor requirements not yet defined
  3. 1992 High

    Dissecting the DNA-binding apparatus into a tripartite domain structure explained how HNF1A achieves sequence-specific recognition of the GTTAATNATTAAC palindrome and high-affinity binding.

    Evidence Deletion mutagenesis of recombinant protein with EMSA and dimerization assays, plus NMR/CD of the N-terminal dimerization peptide

    PMID:1337605 PMID:1356766

    Open questions at the time
    • Dimerization domain solution structure not uniquely determined from NOE data
    • Atomic-resolution structure of the full DNA complex not yet obtained
  4. 1993 High

    Solving the homeodomain structure showed the 21-residue insertion forms a second hydrophobic core that is dispensable for DNA contact, clarifying how an atypical homeodomain retains classical major-groove recognition.

    Evidence X-ray crystallography at 2.8 Å with structural comparison to the engrailed homeodomain-DNA complex; later confirmed by NMR solution structure

    PMID:8491173 PMID:9126845

    Open questions at the time
    • Full-length protein-DNA complex structure not determined
    • Role of the insertion in dimer geometry or cofactor binding unaddressed
  5. 1994 Medium

    Identifying that HNF1A represses its own promoter via its DNA-binding domain plus a distinct C-terminal region established negative autoregulation as a tuning mechanism.

    Evidence Transfection reporter assays with HNF1A deletion mutants in hepatoma cells; EMSA showed no direct binding to the distal promoter

    PMID:7937157

    Open questions at the time
    • Lack of direct binding leaves the repression mechanism indirect and undefined
    • Single-lab, single cell type
  6. 1996 Medium

    Placing HNF4 upstream of HNF1A in a transcriptional hierarchy answered how HNF1A is positioned within an endoderm differentiation cascade.

    Evidence HNF4 mRNA microinjection into Xenopus eggs and mutational analysis of HNF1A promoter HNF4 sites with reporter assays

    PMID:8413240 PMID:8808405

    Open questions at the time
    • Conservation of the exact HNF4-HNF1A wiring in mammalian beta cells not directly shown here
    • Maternal OZ-1 contribution mammalian relevance unclear
  7. 1997 High

    Reconstituting DCoH-HNF1A heterotetramers showed how a cofactor stabilizes HNF1A on DNA, enables binding to weak sites, and blocks RNA interactions, defining post-DNA-binding modulation.

    Evidence Purified recombinant protein binding assays, EMSA with heterotetramers, and dehydratase enzymatic assays; corroborated by Xenopus XDCoH binding and transactivation/colocalization studies

    PMID:7743933 PMID:8995521

    Open questions at the time
    • Physiological significance of the HNF1A-RNA interaction that DCoH abolishes unknown
    • Whether DCoH enzymatic activity is functionally coupled to transcription unresolved
  8. 2000 High

    Linking a dominant-negative MODY3 mutant to a specific set of repressed metabolic targets connected HNF1A dysfunction mechanistically to impaired insulin secretion.

    Evidence Inducible dominant-negative HNF1A-P291fsinsC in INS-1 cells with gene/enzyme expression, pyruvate oxidation, mitochondrial membrane potential, and insulin secretion assays

    PMID:10944108

    Open questions at the time
    • Whether P291fsinsC acts dominant-negatively in patients or via haploinsufficiency later contested
    • UCP2 upregulation mechanism not defined
  9. 2002 High

    Identifying Mirk/Dyrk1B as a kinase that phosphorylates and activates HNF1A established a signaling input controlling HNF1A transcriptional potency.

    Evidence Yeast two-hybrid, co-IP, GST pull-down, kinase-dead mutants, and β-fibrinogen promoter reporter assays; MKK3 placed upstream

    PMID:11980910

    Open questions at the time
    • Phosphorylation sites on HNF1A not mapped
    • Tissue contexts where this pathway operates not established
  10. 2003 Medium

    Showing HNF1A can functionally replace vHNF1 in visceral endoderm formation established that HNF1-family developmental specificity arises from expression patterns rather than intrinsic activity differences.

    Evidence Stable HNF1A reexpression in vHnf1-/- embryonic stem cells with embryoid body differentiation and marker analysis

    PMID:12860991

    Open questions at the time
    • Whether interchangeability holds in other tissues untested
    • Single ESC differentiation system
  11. 2016 High

    Genome-wide and targeted analyses across pancreas, liver, and epididymis identified direct HNF1A targets and showed mutations reduce both activity and nuclear localization, broadening HNF1A's transcriptional program and MODY3 mechanisms.

    Evidence ChIP-seq plus RNA-seq with pH assays in epididymal epithelium; reporter/EMSA on glucokinase and PCSK9; transfection of MODY3 mutants in HeLa with activity and immunofluorescence readouts; Hnf1a-/- suppressor genetics

    PMID:11460882 PMID:26808453 PMID:26853433 PMID:27667715 PMID:28204827

    Open questions at the time
    • Mechanistic basis of impaired nuclear localization for specific mutants not defined
    • Moda1 suppressor causal gene not identified
  12. 2018 Medium

    Defining HNF1A roles in pancreatic cancer stem cells and in modifying MODY3 onset extended its functions to tumor maintenance and genotype-phenotype variation.

    Evidence Knockdown/overexpression with tumorsphere and xenograft assays linking HNF1A to OCT4 and CASC2/PTEN-Akt; cohort meta-analysis of the I27L modifier in PTV carriers

    PMID:28865121 PMID:29895593 PMID:30074477

    Open questions at the time
    • Direct HNF1A targets driving the cancer stem cell program incompletely defined
    • I27L modifier effect lacks direct mechanistic assay
  13. 2022 High

    Patient iPSC beta-cell models and the HASTER cis-regulatory locus revealed that precise HNF1A dosage — maintained by feedback and disrupted by NMD-driven haploinsufficiency or distinct mutant phenotypes — governs beta-cell metabolic coupling and secretion.

    Evidence MODY3 patient hiPSC beta cells (H126D, R272C, P291fsinsC) with ChIP-seq, RNA-seq, glucose uptake/ATP, calcium imaging, pharmacological rescue, and NMD inhibition; Haster mutant mice with ChIP-seq and glucose tolerance tests

    PMID:31145732 PMID:34035238 PMID:36202974 PMID:36563694

    Open questions at the time
    • Reconciliation of dominant-negative versus haploinsufficiency mechanisms across mutations incomplete
    • How HASTER-mediated feedback is molecularly enforced not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how HNF1A integrates upstream signaling, cofactor availability, and HASTER feedback into mutation-specific beta-cell phenotypes that range from hypersecretion to failure.
  • No unified model linking specific HNF1A mutation class to temporal beta-cell trajectory
  • Phosphorylation sites and full cofactor regulatory network undefined
  • Structure of full-length HNF1A-DCoH-DNA assembly unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 6 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1430728 Metabolism 3 R-HSA-1266738 Developmental Biology 2
Partners
DYRK1BHNF1BHNF4APCBD1
Complex memberships
HNF1A homodimerHNF1A-DCoH heterotetramerHNF1A-vHNF1 (HNF1B) heterodimerMirk-DCoHm-HNF1A ternary complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 HNF1A (LFB1/HNF1) and vHNF1 (LFB3) readily form heterodimers both in vitro and in nuclear extracts, and vHNF1 can transactivate the albumin promoter; heterodimer formation was demonstrated by biochemical characterization of vHNF1/HNF1 complexes in nuclear extracts of kidney, liver, and cell lines. In vitro dimerization assays, nuclear extract co-immunoprecipitation/biochemical characterization, transfection reporter assays The EMBO journal High 1673925 1673926
1992 HNF1A (LFB1/HNF1) binds DNA as a homodimer or heterodimer with vHNF1; the DNA-binding domain has a tripartite structure: an N-terminal dimerization domain (domain A), a POU-A-related domain (domain B), and an atypical extended homeodomain (domain C). Domain B plus the homeodomain are required and sufficient for sequence-specific recognition of the inverted palindrome GTTAATNATTAAC; domain A increases binding affinity but does not affect dimer geometry. Deletion mutagenesis of recombinant protein, DNA-binding assays (gel shift/EMSA), dimerization assays The EMBO journal High 1356766
1992 The dimerization domain of HNF1A (LFB1/HNF1α) resides in the 32 N-terminal residues and forms a structure consistent with a four-helix bundle, as determined by NMR and CD spectroscopy of synthetic peptides; LFB1/LFB3 heterodimer peptides were also characterized. NMR spectroscopy, CD spectroscopy of synthetic dimerization domain peptides Protein engineering Medium 1337605
1993 X-ray crystal structure of the 99-residue homeodomain of LFB1/HNF1 solved to 2.8 Å resolution revealed the same helix topology as classical homeodomains, with a 21-residue insertion extending helix 2; the extra residues are not involved in DNA binding, and comparison with the engrailed homeodomain-DNA complex indicates similar major-groove contacts. X-ray crystallography at 2.8 Å resolution The EMBO journal High 8491173
1997 NMR solution structure of the non-classical homeodomain of LFB1/HNF1 determined; the globular fold contains three well-defined helices with a 21-residue insertion between helices II and III forming a second hydrophobic core; studies of complex formation with operator DNA half-site provided initial information on the DNA-binding mode. NMR spectroscopy (15N- and 13C-labelled protein), 1356 NOE constraints Journal of molecular biology High 9126845
1990 HNF1A (HNF1/LFB1) expression in hepatoma cells is regulated primarily at the transcriptional level: run-on transcription assays in isolated nuclei showed that HNF1A mRNA is absent in dedifferentiated hepatoma variants and in extinguished somatic hybrids, and reappears in revertants to the hepatic phenotype. vHNF1 protein is encoded by a distinct gene from HNF1A. Northern blotting, nuclear run-on transcription assays The EMBO journal High 2357969
1993 The Xenopus homolog of HNF1A (XLFB1/HNF1) is expressed in liver, stomach, intestine, colon, and kidney; XLFB1 protein appears in regions of the embryo corresponding to liver diverticulum, stomach, gut, and pronephros from the gastrula stage onward, consistent with a role in determination/differentiation of specific cell types during organogenesis. Structural comparison shows conservation of the dimerization helix, POU-A-related domain, homeodomain, and serine/threonine-rich activation domain between Xenopus and mammals. cDNA cloning, monoclonal antibody immunolocalization, in situ hybridization, RT-PCR Molecular and cellular biology Medium 8417340
1993 The HNF1A (LFB1) promoter contains an element with CCNCTCTC core consensus sequence that is essential for embryonic activation in Xenopus; this element is recognized by maternal factor OZ-1. LFB1 promoter analysis also identified potential autoregulation by LFB1 itself and regulation by HNF4. Reporter gene injection into Xenopus eggs, deletion analysis of Xenopus and rat LFB1 promoters, transfection assays Molecular and cellular biology Medium 8413240
1994 HNF1A (LFB1/HNF1) acts as a transcriptional repressor of its own promoter in cultured hepatoma cells: exogenously added LFB1/HNF1 protein down-regulates its own promoter activity, requiring both the intact N-terminal DNA-binding domain and a distinct 60-aa C-terminal region separate from the activation domains. Purified LFB1/HNF1 showed no specific binding to the -3.5 kb promoter sequence in vitro. Transfection reporter assays, deletion mutagenesis of HNF1A protein, in vitro binding (EMSA) — negative for direct binding Nucleic acids research Medium 7937157
1996 HNF4 acts upstream of HNF1A (HNF1α) in a transcriptional hierarchy during Xenopus development: HNF4 binding sites in the HNF1α promoter are essential for proper embryonic activation; injection of HNF4 mRNA into fertilized Xenopus eggs ectopically activates the endogenous HNF1α gene, and HNF4 is present as a maternal protein with an animal-to-vegetal gradient. mRNA microinjection into Xenopus eggs, mutational analysis of HNF1α promoter, reporter gene assays Mechanisms of development Medium 8808405
1997 DCoH (dimerization cofactor of HNF1α) forms stable heterotetramers with HNF1A dimers (two DCoH molecules per HNF1A dimer), stabilizes HNF1A/DNA complexes, promotes HNF1A binding to suboptimal DNA targets, and abolishes HNF1A-RNA interactions; DCoH retains its enzymatic activity (pterin-4α-carbinolamine dehydratase, involved in tetrahydrobiopterin regeneration) when complexed with HNF1A. Purified recombinant protein binding assays, EMSA with HNF1A/DCoH heterotetramers, enzymatic activity assays Journal of molecular biology High 8995521
1995 The Xenopus DCoH homolog (XDCoH) is a maternal protein that enhances LFB1/HNF1A-dependent transactivation in transfection experiments and interacts directly with both LFB1 (HNF1A) and LFB3 (vHNF1) in vitro; XDCoH enters cell nuclei when zygotic transcription begins and co-localizes with LFB1/LFB3 in hepatocytes, gut, and pronephric cells during embryogenesis. cDNA cloning, in vitro binding assays, transfection reporter assays, immunostaining/immunolocalization in embryos Development (Cambridge, England) Medium 7743933
2000 The MODY3-associated dominant-negative mutant HNF1A-P291fsinsC competes with endogenous HNF1A for cognate DNA-binding sites in beta cells and reduces expression of insulin, GLUT2, L-pyruvate kinase, aldolase B, HMG-CoA reductase, and mitochondrial 2-oxoglutarate dehydrogenase E1 subunit, while dramatically increasing UCP2 expression; this altered gene expression profile inhibits glucose- and leucine-stimulated insulin secretion by impairing mitochondrial ATP production and membrane hyperpolarization. Inducible expression of dominant-negative HNF1A in INS-1 cells, RT-PCR and protein analysis, enzymatic activity assays, [14C]pyruvate oxidation, insulin secretion assays, mitochondrial membrane potential measurements The EMBO journal High 10944108
2002 Mirk/Dyrk1B kinase phosphorylates HNF1A and enhances its transcriptional activity in a kinase-activity-dependent manner; Mirk binds to a specific region within the CREB-binding protein-binding region of HNF1A; DCoHm (a muscle-expressed DCoH family member) bridges Mirk and HNF1A in a ternary complex; Mirk kinase activity is activated by the upstream MAPK kinase MKK3. Yeast two-hybrid screening, co-immunoprecipitation, GST pull-down, reporter gene assay (beta-fibrinogen promoter), kinase-inactive Mirk mutants, deletion mutants The Journal of biological chemistry High 11980910
2004 HNF1A binds to a mutation-created site in the HBV core promoter double mutant (A1765T/G1767A) and suppresses precore RNA expression from this mutant promoter; HNF1A had no effect on the wild-type HBV core promoter, distinguishing its activity from HNF4 which stimulated both wild-type and mutant promoters. Transfection reporter assays in Huh7 cells, gel shift assays (EMSA), HBV genomic constructs with/without X protein Journal of virology Medium 15194767
2003 Forced expression of HNF1A in vHnf1-deficient embryonic stem cells fully restores formation of a mature visceral endoderm with correct expression of both early and late markers; HNF1A functionally replaces both vHNF1 isoforms in this context, indicating that their distinct developmental roles are mainly due to differences in expression patterns rather than intrinsic biochemical activities. Stable reexpression of HNF1A in vHnf1-/- ESCs, embryoid body differentiation, marker gene expression analysis The Journal of biological chemistry Medium 12860991
2017 HNF1α (HNF1A) is a positive transcriptional regulator of hepatic PCSK9 expression; liver-specific adenoviral shRNA knockdown of HNF1α in hamsters blunted rosuvastatin-induced elevation of serum and hepatic PCSK9 levels and increased liver LDL receptor protein, leading to reduced circulating cholesterol. HNF1α protein levels were increased by rosuvastatin treatment without a corresponding change in HNF1α mRNA. Adenoviral shRNA liver-specific knockdown in hamsters, Western blotting, qPCR, serum PCSK9 and cholesterol measurements International journal of molecular medicine Medium 28204827
2018 HNF1A is required for pancreatic cancer stem cell (PCSC) properties: depletion of HNF1A in pancreatic cancer cells caused growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression; HNF1A overexpression increased PCSC markers and tumorsphere formation; xenograft depletion impaired tumor growth and depleted PCSC marker-positive cells. siRNA/shRNA knockdown, overexpression, tumorsphere assays, xenograft tumor growth, flow cytometry for PCSC markers, bioinformatic analysis of PCSC gene signature eLife Medium 30074477
2020 HNF1α modulates glucagon secretion in pancreatic α-cells through transcriptional regulation of Slc5a1 (encoding SGLT1): HNF1α activated the Slc5a1 promoter in αTC1-6 cells; Hnf1a-/- islets showed decreased Slc5a1 expression; SGLT1 inhibition suppressed glucose-stimulated glucagon secretion, and had no additional inhibitory effect in HNF1α-deficient cells, placing HNF1α upstream of SGLT1 in glucagon regulation. Hnf1a knockout mice, luciferase reporter assay (Slc5a1 promoter), glucagon secretion assay, SGLT1 inhibitor, islet gene expression Biochimica et biophysica acta. Molecular basis of disease High 32711050
2021 MODY3 patient-specific HNF1A+/H126D hiPSC-derived β-like cells show decreased GLUT2 expression associated with reduced glucose uptake and ATP production; genome-wide ChIP-seq and RNA-seq on HNF1A+/H126D endocrine progenitors revealed numerous HNF1A gene targets affected by the mutation; molecular dynamics simulations predicted the H126D mutation compromises DNA binding. hiPSC differentiation to β-cells, RNA-seq, ChIP-seq, glucose uptake assay, ATP measurement, molecular dynamics simulation Nature communications High 34035238
2022 MODY3 patient-specific HNF1A+/R272C hiPSC-derived β-cells hypersecrete insulin (both in vitro and in vivo after transplantation) prior to eventual β-cell failure; reduced expression of KATP channel subunits leads to increased calcium signaling and enhanced membrane depolarization; pharmacological targeting of ATP-sensitive potassium channels or low-voltage-activated calcium channels rescues the hypersecretion phenotype. Patient hiPSC differentiation, in vitro insulin secretion, xenotransplantation into mice, calcium imaging, pharmacological rescue (KATP and Ca2+ channel blockers), gene expression analysis Cell stem cell High 36563694
2022 The HASTER lncRNA promoter DNA (not the lncRNA itself) acts as a cis-regulatory element that maintains cell-specific physiological HNF1A concentrations through positive and negative feedback loops; HASTER-dependent negative feedback prevents HNF1A from binding to inappropriate genomic regions; Haster mutant mice show variegated HNF1A silencing or overexpression in β-cells leading to hyperglycaemia. Mouse and human cell models, Haster mutant mice, ChIP-seq (HNF1A binding), promoter-enhancer interaction mapping, glucose tolerance tests Nature cell biology High 36202974
2016 HNF1A mutations (p.R171G, p.G245R, p.R263H) cause MODY3 by reducing both transcriptional activity and nuclear localization of HNF1A protein in transfected HeLa cells; the common variant p.S487N further reduces function of p.R271Q in a double mutant by additionally impairing both activity and localization. Transfection of mutant HNF1A constructs in HeLa cells, reporter gene assay (transcriptional activity), immunofluorescence (nuclear localization) Clinical genetics Medium 26853433
2016 HNF1A controls PCSK9 transcription via direct HNF1 binding sites in the PCSK9 promoter (by inference from established HNF1 site in PCSK9 promoter); liver-specific HNF1α knockdown blunts statin-induced PCSK9 upregulation, demonstrating that statin-mediated PCSK9 induction is HNF1α-dependent and that HNF1α is a positive regulator of PCSK9. Adenoviral shRNA knockdown, PCSK9 mRNA/protein measurements, serum cholesterol assays — this finding is reported in PMID:28204827 (2017) International journal of molecular medicine Medium 28204827
2016 HNF1A regulates critical epithelial transport genes in the epididymis; ChIP-seq in human epididymis epithelial cells identified direct HNF1A target genes; siRNA depletion of both HNF1α and HNF1β caused differential expression of 1892 transcripts, with downregulated genes enriched for epithelial transport of water, phosphate, and bicarbonate; measurement of intracellular pH confirmed HNF1 role in regulating luminal environment. ChIP-seq, RNA-seq after siRNA knockdown, open chromatin mapping (ATAC-seq equivalent), intracellular pH measurements Molecular and cellular endocrinology High 26808453
2016 A genetic suppressor locus (Moda1) on mouse chromosome 3 completely suppresses diabetes in Hnf1a-deficient mice on C3H/CBA backgrounds; the mechanism involves restoration of postnatal islet growth that is defective in diabetic-prone HNF1α-deficient strains; Moda1 contains 11 genes with non-synonymous SNPs and interacts epistatically with loci on chromosomes 4, 11, and 18. Genome scan of Hnf1a-/- congenic mouse strains, islet histology/morphometry, epistasis analysis Scientific reports Medium 27667715
2001 HNF1A binds to the glucokinase (GK) promoter and contributes to tissue-specific GK expression: EMSA confirmed HNF1A binding to GK promoter sequences, and transfection of GK promoter-reporter constructs showed high HNF1A-driven activity in GK-expressing liver and pancreatic beta cell lines but minimal activity in HNF1-negative cells. EMSA, transfection reporter assays, RT-PCR for HNF1 and GK expression Experimental & molecular medicine Medium 11460882
2018 The common HNF1A variant I27L (rs1169288) modifies age at diabetes diagnosis in HNF1A-MODY patients with protein-truncating variants: meta-analysis of two independent cohorts (n=444 with PTVs) showed each 27L allele associated with 1.6-year earlier onset, demonstrating intragenic modifier effects on HNF1A haploinsufficiency. Meta-analysis of two independent cohorts, stratification by mutation type (PTV vs. missense) Diabetes Medium 29895593
2019 Nonsense-mediated mRNA decay (NMD) degrades the P291fsinsC mutant HNF1A transcript in MODY3 patient-derived iPSC-derived pancreatic lineage cells; mutant transcripts were present at much lower frequency than wild-type but increased upon cycloheximide (NMD inhibitor) treatment; truncated mutant protein was undetectable, suggesting MODY3 caused by haploinsufficiency rather than dominant-negative mechanism for this mutation. MODY3 patient iPSC differentiation to pancreatic beta cells, HNF1A transcript cloning/sequencing, cycloheximide treatment, Western blotting PloS one Medium 31145732
2018 HNF1A positively regulates CASC2 lncRNA expression through direct binding to an HNF1A-responsive element (CASC2-HNF1A RE) in the CASC2 gene promoter; CASC2 suppresses pancreatic cancer cell proliferation via PTEN/Akt signaling downstream of HNF1A. Luciferase reporter assay with CASC2 promoter, site-directed mutagenesis of HNF1A RE, siRNA knockdown, Western blotting for PTEN/Akt pathway Journal of cellular biochemistry Medium 28865121

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Intratumoral Tcf1+PD-1+CD8+ T Cells with Stem-like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity 1317 30635237
2016 The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Science immunology 524 28018990
1991 vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. The EMBO journal 276 1673926
1992 HNF1, a homeoprotein member of the hepatic transcription regulatory network. BioEssays : news and reviews in molecular, cellular and developmental biology 206 1365913
2021 TCF1 in T cell immunity: a broadened frontier. Nature reviews. Immunology 201 34127847
2016 Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nature immunology 189 27111144
1991 LFB3, a heterodimer-forming homeoprotein of the LFB1 family, is expressed in specialized epithelia. The EMBO journal 181 1673925
2020 Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells. Nature immunology 177 33139915
1992 Expression patterns of vHNF1 and HNF1 homeoproteins in early postimplantation embryos suggest distinct and sequential developmental roles. Development (Cambridge, England) 151 1363228
2015 TCF1 Is Required for the T Follicular Helper Cell Response to Viral Infection. Cell reports 149 26365183
2022 Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop. Cancer cell 140 36423635
1990 Hepatocyte dedifferentiation and extinction is accompanied by a block in the synthesis of mRNA coding for the transcription factor HNF1/LFB1. The EMBO journal 135 2357969
2018 Suppression of Tcf1 by Inflammatory Cytokines Facilitates Effector CD8 T Cell Differentiation. Cell reports 131 29466737
1992 LFB1 and LFB3 homeoproteins are sequentially expressed during kidney development. Development (Cambridge, England) 131 1350532
2021 Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 130 34534464
2015 TCF1 links GIPR signaling to the control of beta cell function and survival. Nature medicine 126 26642437
2000 Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction. The EMBO journal 114 10944108
2018 TCF1 expression marks self-renewing human CD8+ T cells. Blood advances 102 30021780
2019 TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases. Cell reports 94 31216480
2021 Role of TCF-1 in differentiation, exhaustion, and memory of CD8+ T cells: A review. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 93 33913198
2004 Regulation of hepatitis B virus core promoter by transcription factors HNF1 and HNF4 and the viral X protein. Journal of virology 91 15194767
2019 Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells. The Journal of experimental medicine 90 30837262
2007 Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth. Endocrine development 88 17923767
2019 Control of Lymphocyte Fate, Infection, and Tumor Immunity by TCF-1. Trends in immunology 84 31734149
1997 Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes 81 9166684
2009 Species-specific differences in the expression of the HNF1A, HNF1B and HNF4A genes. PloS one 75 19924231
2023 Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy. Cancer cell 70 37625402
2021 Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture. Nature communications 70 34615872
2023 Characteristics and anatomic location of PD-1+TCF1+ stem-like CD8 T cells in chronic viral infection and cancer. Proceedings of the National Academy of Sciences of the United States of America 69 37782797
2022 TCF-1: a maverick in T cell development and function. Nature immunology 69 35487986
1993 The X-ray structure of an atypical homeodomain present in the rat liver transcription factor LFB1/HNF1 and implications for DNA binding. The EMBO journal 68 8491173
2010 TCF1 and beta-catenin regulate T cell development and function. Immunologic research 64 20082155
2020 The Transcription Factor TCF1 in T Cell Differentiation and Aging. International journal of molecular sciences 63 32899486
2002 Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. The Journal of biological chemistry 62 11980910
2019 Novel insights into genetics and clinics of the HNF1A-MODY. Endocrine regulations 61 31517624
2018 HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. eLife 60 30074477
2014 From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells. Immunologic research 59 24847765
2021 Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells. Nature communications 57 34035238
2022 Tcf1-CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis. Nature immunology 53 35882936
1993 Developmental regulation and tissue distribution of the liver transcription factor LFB1 (HNF1) in Xenopus laevis. Molecular and cellular biology 51 8417340
2001 Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. Diabetologia 50 11270685
2010 Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage. Diabetes 48 20393147
2024 Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision. Immunity 47 38301652
2022 HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus. Frontiers in endocrinology 46 35299962
2022 HNF1A Mutations and Beta Cell Dysfunction in Diabetes. International journal of molecular sciences 44 35328643
2020 Tcf1+ cells are required to maintain the inflationary T cell pool upon MCMV infection. Nature communications 41 32385253
2018 HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. Journal of cellular biochemistry 41 28865121
1993 Elements and factors involved in tissue-specific and embryonic expression of the liver transcription factor LFB1 in Xenopus laevis. Molecular and cellular biology 41 8413240
1992 A POU-A related region dictates DNA binding specificity of LFB1/HNF1 by orienting the two XL-homeodomains in the dimer. The EMBO journal 41 1356766
2019 DC-SIGN-LEF1/TCF1-miR-185 feedback loop promotes colorectal cancer invasion and metastasis. Cell death and differentiation 40 31217502
2022 TCF1+PD-1+ tumour-infiltrating lymphocytes predict a favorable response and prolonged survival after immune checkpoint inhibitor therapy for non-small-cell lung cancer. European journal of cancer (Oxford, England : 1990) 39 35970031
2024 Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy. Nature immunology 38 39327500
2017 Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLoS genetics 37 28346462
2016 Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors. The Journal of biological chemistry 37 27044748
2024 NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment. Cell reports 36 38451819
2020 Neddylation inhibitor MLN4924 has anti-HBV activity via modulating the ERK-HNF1α-C/EBPα-HNF4α axis. Journal of cellular and molecular medicine 36 33263949
2008 Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabetic medicine : a journal of the British Diabetic Association 36 18513305
1996 Transcriptional hierarchy in Xenopus embryogenesis: HNF4 a maternal factor involved in the developmental activation of the gene encoding the tissue specific transcription factor HNF1 alpha (LFB1). Mechanisms of development 36 8808405
2022 The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nature cell biology 34 36202974
1997 The bifunctional protein DCoH modulates interactions of the homeodomain transcription factor HNF1 with nucleic acids. Journal of molecular biology 34 8995521
2007 Expression of HNF-4alpha (MODY1), HNF-1beta (MODY5), and HNF-1alpha (MODY3) proteins in the developing mouse pancreas. Gene expression patterns : GEP 32 17996499
1995 Developmental expression of the maternal protein XDCoH, the dimerization cofactor of the homeoprotein LFB1 (HNF1). Development (Cambridge, England) 32 7743933
2018 Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatric diabetes 31 29493090
2003 Functions of HNF1 family members in differentiation of the visceral endoderm cell lineage. The Journal of biological chemistry 31 12860991
2015 Inhibition of β-catenin-TCF1 interaction delays differentiation of mouse embryonic stem cells. The Journal of cell biology 30 26459597
1994 Lowered amounts of the tissue-specific transcription factor LFB1 (HNF1) correlate with decreased levels of glutathione S-transferase alpha messenger RNA in human renal cell carcinoma. Cancer research 30 8118822
2021 The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude. The Journal of experimental medicine 29 33857289
2021 TCF-1 maintains CD8+ T cell stemness in tumor microenvironment. Journal of leukocyte biology 29 34047386
2017 Hepatic HNF1 transcription factors control the induction of PCSK9 mediated by rosuvastatin in normolipidemic hamsters. International journal of molecular medicine 29 28204827
2021 The E protein-TCF1 axis controls γδ T cell development and effector fate. Cell reports 26 33535043
2016 Structure-function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes. Clinical genetics 26 26853433
2023 TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Science immunology 25 37801516
2015 TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax. Proceedings of the National Academy of Sciences of the United States of America 24 25646419
2014 Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer. Oncology reports 24 24968817
2024 Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state. Immunity 23 39447575
2003 Tcf-1 expression during Xenopus development. Gene expression patterns : GEP 23 12711535
2022 An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells. Cell stem cell 22 36563694
2001 HNF1 and/or HNF3 may contribute to the tissue specific expression of glucokinase gene. Experimental & molecular medicine 22 11460882
2021 HNF1A regulates colorectal cancer progression and drug resistance as a downstream of POU5F1. Scientific reports 21 33990627
2018 The Common HNF1A Variant I27L Is a Modifier of Age at Diabetes Diagnosis in Individuals With HNF1A-MODY. Diabetes 21 29895593
2015 Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells. Molecular immunology 21 26490636
2010 Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report. Diabetes care 21 20705777
2020 HNF1α controls glucagon secretion in pancreatic α-cells through modulation of SGLT1. Biochimica et biophysica acta. Molecular basis of disease 20 32711050
2008 Variant HNF1 modulates epithelial plasticity of normal and transformed ovary cells. Neoplasia (New York, N.Y.) 20 19048126
2022 METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis. Human cell 19 36401086
2017 Knockdown of lncRNA HNF1A-AS1 inhibits oncogenic phenotypes in colorectal carcinoma. Molecular medicine reports 19 28791380
2021 Tcf1 Sustains the Expression of Multiple Regulators in Promoting Early Natural Killer Cell Development. Frontiers in immunology 17 34917097
2016 HNF1 regulates critical processes in the human epididymis epithelium. Molecular and cellular endocrinology 17 26808453
1997 The NMR solution structure of the non-classical homeodomain from the rat liver LFB1/HNF1 transcription factor. Journal of molecular biology 17 9126845
2024 TCF1-positive and TCF1-negative TRM CD8 T cell subsets and cDC1s orchestrate melanoma protection and immunotherapy response. Journal for immunotherapy of cancer 16 38969523
2020 Long Noncoding RNA HNF1A-AS1 Regulates Osteosarcoma Advancement Through Modulating the miR-32-5p/HMGB1 Axis. Cancer biotherapy & radiopharmaceuticals 16 32706998
2017 A Novel miR-24-TCF1 Axis in Modulating Effector T Cell Responses. Journal of immunology (Baltimore, Md. : 1950) 16 28404635
2023 Liver X receptor controls follicular helper T cell differentiation via repression of TCF-1. Proceedings of the National Academy of Sciences of the United States of America 15 36802434
2023 TCF-1 Is Required for CD4 T Cell Persistence Functions during AlloImmunity. International journal of molecular sciences 15 36901757
2021 PIWI-interacting RNA-23210 protects against acetaminophen-induced liver injury by targeting HNF1A and HNF4A. Biochemical pharmacology 15 34968487
2016 A suppressor locus for MODY3-diabetes. Scientific reports 15 27667715
1994 LFB1/HNF1 acts as a repressor of its own transcription. Nucleic acids research 15 7937157
1992 The dimerization domain of LFB1/HNF1 related transcription factors: a hidden four helix bundle? Protein engineering 15 1337605
2019 Expression of LEF1 and TCF1 (TCF7) proteins associates with clinical progression of nasopharyngeal carcinoma. Journal of clinical pathology 14 30918012
2019 Expression of mutant mRNA and protein in pancreatic cells derived from MODY3- iPS cells. PloS one 14 31145732

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