Affinage

HNF1A

Hepatocyte nuclear factor 1-alpha · UniProt P20823

Length
631 aa
Mass
67.4 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HNF1A is a liver- and pancreas-enriched homeodomain transcription factor that dimerizes through a unique N-terminal dimerization domain and binds DNA via a tripartite architecture comprising a POU-A-related region and a non-classical homeodomain with a 21-residue inter-helical insertion (PMID:2216777, PMID:1356766, PMID:8491172). It forms homodimers or heterodimers with HNF1β, is stabilized on DNA by the cofactor DCoH, and is phosphorylated by Mirk/Dyrk1B to enhance transcriptional output (PMID:1673926, PMID:8995521, PMID:11980910). In pancreatic β cells, HNF1A directly controls genes required for glucose-stimulated insulin secretion—including GLUT2, KATP channel subunits, and mitochondrial metabolic enzymes—and its dosage is maintained by a cis-regulatory feedback circuit at the HASTER lncRNA promoter; heterozygous loss-of-function mutations cause maturity-onset diabetes of the young type 3 (MODY3) through haploinsufficiency (PMID:10944108, PMID:36563694, PMID:36202974, PMID:12530534). In pancreatic acinar cells, HNF1A recruits the histone demethylase KDM6A to enhancers to maintain differentiation and suppress oncogenic programs, functioning as a tumor suppressor whose loss cooperates with oncogenic Kras to promote pancreatic ductal adenocarcinoma (PMID:32154941).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1990 High

    Identification of HNF1A as a novel dimerizing homeoprotein established that a distal dimerization domain and a homeodomain-like region are both necessary for sequence-specific DNA binding, defining a new transcription factor subclass.

    Evidence Protein purification, cDNA cloning, and in vitro DNA-binding/mutagenesis assays

    PMID:2216777

    Open questions at the time
    • Three-dimensional arrangement of the dimerization and DNA-binding domains was unknown
    • No in vivo target genes had been identified
  2. 1991 High

    Demonstration that HNF1A heterodimerizes with HNF1β on the same DNA element and activates shared promoters revealed combinatorial regulation at HNF1 sites across tissues.

    Evidence In vitro dimerization, co-immunoprecipitation from nuclear extracts, and reporter assays in two independent labs

    PMID:1673925 PMID:1673926

    Open questions at the time
    • Relative contributions of homodimers vs. heterodimers in different tissues were undefined
    • Structural basis of dimerization selectivity was unknown
  3. 1993 High

    The NMR structure of the HNF1A homeodomain revealed a non-classical fold with a 21–23-residue insertion between helices II and III, explaining why HNF1A does not fit canonical homeoprotein classification and redefining its DNA-recognition mode.

    Evidence NMR spectroscopy with isotope-labeled recombinant protein

    PMID:8491172 PMID:9126845

    Open questions at the time
    • Full-length dimer–DNA complex structure was not determined
    • Contribution of POU-A domain to DNA specificity was inferred but not structurally resolved
  4. 1992 High

    Systematic domain-deletion analysis showed that the POU-A-related domain (B) orients the two homeodomains within the dimer and dictates DNA-binding specificity, while the dimerization domain (A) increases affinity without altering geometry.

    Evidence Recombinant protein domain deletions with in vitro DNA-binding specificity analysis

    PMID:1356766

    Open questions at the time
    • Structural basis of POU-A–homeodomain cooperativity remained unresolved
  5. 1996 Medium

    Establishing that HNF4α activates the HNF1A promoter in Xenopus defined a transcriptional hierarchy in which HNF4 initiates HNF1A expression during early development.

    Evidence mRNA microinjection into Xenopus embryos and HNF1A promoter mutagenesis

    PMID:8808405

    Open questions at the time
    • Hierarchy was shown in Xenopus, not mammalian models
    • Whether other upstream factors are required was not addressed
  6. 1997 High

    Biochemical reconstitution of the DCoH–HNF1A heterotetramer showed that DCoH stabilizes DNA-bound HNF1A, promotes binding to suboptimal sites, and abolishes HNF1A–RNA interactions, defining DCoH as a bifunctional cofactor that retains enzymatic activity.

    Evidence Purified recombinant DCoH and HNF1A proteins, gel-shift and enzymatic assays

    PMID:8995521

    Open questions at the time
    • In vivo stoichiometry and tissue-specific relevance of DCoH cofactor function were not established
    • Biological role of HNF1A–RNA interaction remains unclear
  7. 1999 High

    Functional classification of ten MODY3 missense and truncation mutants revealed that loss of DNA binding, protein stability, or transactivation each independently causes disease, and some truncation mutants act as dominant negatives—though subsequent work favored haploinsufficiency.

    Evidence Transient transfection, EMSA, and protein stability assays with disease-derived mutants

    PMID:10585442 PMID:12530534

    Open questions at the time
    • Dominant-negative vs. haploinsufficiency debate was not definitively settled in vivo
    • mRNA instability mechanism for frameshift mutants was not fully characterized
  8. 2000 High

    Inducible expression of a MODY3 dominant-negative HNF1A in β cells identified GLUT2, L-pyruvate kinase, mitochondrial OGDH, and UCP2 as targets, and directly linked HNF1A dysfunction to impaired mitochondrial ATP production and defective glucose-stimulated insulin secretion.

    Evidence Tet-inducible dominant-negative in INS-1 cells with RT-PCR, metabolic flux, and insulin secretion assays

    PMID:10944108

    Open questions at the time
    • Whether all identified target genes are direct (bound by HNF1A) was not demonstrated
    • In vivo confirmation in primary β cells was lacking
  9. 2002 High

    Identification of Mirk/Dyrk1B as a kinase that phosphorylates HNF1A and enhances its transcriptional activity added post-translational regulation to the HNF1A activation model.

    Evidence Yeast two-hybrid, GST pulldown, co-IP, in vitro kinase assay, and reporter assay with kinase-dead controls

    PMID:11980910

    Open questions at the time
    • Phosphorylation site(s) on HNF1A were mapped to a region but not to individual residues
    • Physiological relevance of Mirk-mediated phosphorylation in β cells was not tested
  10. 2020 High

    Discovery that HNF1A physically recruits KDM6A to acinar enhancers established a chromatin-remodeling mechanism by which HNF1A maintains acinar differentiation and suppresses oncogenic programs; genetic epistasis with Kras demonstrated a tumor-suppressor role in pancreatic cancer.

    Evidence Conditional Hnf1a and Kdm6a KO mice, double mutants with KrasG12D, ChIP-seq, ATAC-seq, RNA-seq, co-IP

    PMID:32154941

    Open questions at the time
    • Whether KDM6A recruitment is direct or via an intermediate complex was not resolved structurally
    • Relevance of HNF1A–KDM6A axis in human PDAC samples was not validated
  11. 2021 High

    Genome-wide ChIP-seq in patient-derived iPSC β cells carrying an HNF1A disease mutation provided the first comprehensive map of HNF1A occupancy in human endocrine progenitors and confirmed GLUT2 as a direct target whose loss impairs glucose uptake and ATP production.

    Evidence MODY3 patient hiPSC-derived β-like cells, ChIP-seq, RNA-seq, glucose uptake and ATP assays, molecular dynamics

    PMID:34035238

    Open questions at the time
    • ChIP-seq was in endocrine progenitors; occupancy in mature human β cells was not profiled
    • Functional validation was limited to a single mutation (H126D)
  12. 2022 High

    Two studies redefined the MODY3 disease mechanism: the HASTER lncRNA promoter acts as a cis-regulatory element enforcing HNF1A dosage homeostasis, and MODY3 β cells show an initial insulin hypersecretion phase (from reduced KATP channels and increased calcium signaling) preceding eventual β-cell failure.

    Evidence Mouse Haster mutants, human iPSC models, chromatin conformation analysis, patient hiPSC β cells with electrophysiology and pharmacological rescue

    PMID:36202974 PMID:36563694

    Open questions at the time
    • Whether the hypersecretion-to-failure transition occurs in human patients in vivo remains to be demonstrated longitudinally
    • Molecular mechanism by which HASTER DNA controls promoter–enhancer topology is not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the full-length HNF1A dimer–DNA–cofactor complex, the complete catalog of direct target genes across tissues, and the in vivo mechanism of the hypersecretion-to-failure transition in MODY3 remain to be established.
  • No full-length HNF1A dimer–DNA crystal/cryo-EM structure exists
  • Direct vs. indirect target genes are not comprehensively distinguished across liver, kidney, intestine, and β cells
  • Longitudinal in vivo evidence for the biphasic MODY3 disease model is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 2 R-HSA-4839726 Chromatin organization 1
Partners
DYRK1BHNF1BHNF4AKDM6APCBD1RXRA
Complex memberships
HNF1A homodimerHNF1A–DCoH heterotetramerHNF1A–HNF1β heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 HNF1A (LFB1/HNF1) contains a distal dimerization domain (domain A) and a homeodomain-like region both required for specific DNA binding; the protein dimerizes in the presence or absence of DNA, placing it as the prototype of a novel subclass of homeoproteins. Protein purification, cDNA cloning, DNA-binding assays, sequence analysis Nucleic acids research High 2216777
1991 HNF1A (vHNF1/LFB3) forms homodimers and heterodimers with HNF1 (LFB1) both in vitro and in nuclear extracts of kidney, liver, and cell lines; the heterodimers bind the same DNA element as HNF1 homodimers and transactivate the albumin promoter. In vitro dimerization assay, co-immunoprecipitation from nuclear extracts, transfection/reporter assay The EMBO journal High 1673925 1673926
1990 HNF1A transcripts are absent in dedifferentiated hepatoma cells and restored in hepatic revertants; run-on transcription shows regulation is primarily at the transcriptional level, and a distinct gene (vHNF1) encodes the lower-MW variant found in dedifferentiated cells. Northern blot, nuclear run-on transcription, cell-line reversion studies The EMBO journal High 2357969
1992 The POU-A-related domain (domain B) of HNF1A, together with the homeodomain (domain C), is required and sufficient for recognition of dyad-symmetry HNF1 binding sites; domain B orients the two XL-homeodomains within the dimer and dictates DNA-binding specificity. Domain A increases binding affinity but does not change dimer geometry. Recombinant protein binding assays, domain-deletion mutants, DNA-binding specificity analysis The EMBO journal High 1356766
1993 NMR structure of the HNF1A (LFB1) homeodomain (residues 195–286) reveals a nonclassical homeodomain with three alpha-helices and a 23-residue insertion between helices II and III that replaces the canonical turn, forming a non-classical helix-turn-helix motif for DNA recognition. NMR spectroscopy (15N, 13C uniform labeling), structure calculation The EMBO journal High 8491172
1997 Refined NMR solution structure of the HNF1A homeodomain confirmed three helices with two hydrophobic cores; one core stabilizes the helix packing as in classical homeodomains and another stabilizes the 21-residue insertion between helices II and III. Initial DNA half-site complex studies provided information on the DNA-binding mode. High-resolution NMR with NOE and dihedral constraints, energy minimization Journal of molecular biology High 9126845
1997 DCoH (dimerization cofactor of HNF1) forms stable heterotetramers with HNF1A dimers; DCoH stabilizes HNF1A/DNA complexes, promotes binding to suboptimal DNA targets, and abolishes HNF1A interactions with RNA. DCoH retains its enzymatic (pterin-4a-carbinolamine dehydratase) activity while complexed with HNF1A. Purified recombinant proteins, gel-shift assay, in vitro binding, enzymatic activity assay Journal of molecular biology High 8995521
1999 Analysis of 10 MODY3 HNF1A missense and truncation mutants reveals distinct functional defects: reduced protein stability, loss of DNA binding, or impaired intrinsic transactivation; three mutants with complete loss of transactivation act as dominant negatives when co-transfected with wild-type HNF1A. Transient transfection, reporter gene assay, gel-retardation (EMSA), protein stability assays The Journal of biological chemistry High 10585442
2000 Inducible expression of the dominant-negative MODY3 mutant HNF1A-P291fsinsC in INS-1 insulinoma cells—competing with endogenous HNF1A for DNA binding—reduces expression of insulin, GLUT2, L-pyruvate kinase, aldolase B, HMG-CoA reductase, and mitochondrial OGDH E1, while dramatically increasing UCP2; this impairs mitochondrial ATP production and inhibits glucose/leucine-stimulated insulin secretion. Inducible expression system (reverse-tet transactivator), RT-PCR, Western blot, enzyme activity assay, 14C-pyruvate oxidation, insulin secretion assay, mitochondrial membrane potential measurement The EMBO journal High 10944108
2002 Mirk/Dyrk1B kinase is activated by MKK3 and forms a complex with DCoHm and HNF1A; Mirk phosphorylates HNF1A adjacent to the Mirk-binding region and enhances HNF1A transcriptional activity in a kinase-activity-dependent manner. Yeast two-hybrid, GST pulldown, co-immunoprecipitation, kinase assay (phosphorylation of HNF1A), reporter gene assay, domain-mapping The Journal of biological chemistry High 11980910
2002 Functional analysis of seven MODY3 HNF1A mutations (Q7X, R171X, AN127, P291fsinsC, R229Q, P447L, T620I) shows none act as dominant negatives; mRNA stability is impaired for AN127, R171X, P291fsinsC, and T547E548fsdelTG independently of NMD, indicating haploinsufficiency as the primary pathogenetic mechanism. Gel retardation (EMSA), reporter gene assay, mRNA stability analysis, transfection Biological chemistry Medium 12530534
2003 Forced expression of HNF1A in vHnf1-deficient embryonic stem cells fully restores formation of mature visceral endoderm with correct expression of early and late markers, demonstrating that HNF1A can functionally replace both vHNF1 isoforms in visceral endoderm differentiation. Stable re-expression in vHnf1-/- ES cells, embryoid body differentiation, gene expression analysis The Journal of biological chemistry High 12860991
2005 HNF1A (and HNF1β) directly bind to the HNF1 element in the ACAT2 promoter in vitro and in vivo; deletion of this element abolishes basal promoter activity and HNF1A-induced transactivation in hepatocellular carcinoma cells, identifying HNF1A as a key liver-specific trans-activator of ACAT2. Promoter deletion constructs, reporter assay, EMSA, chromatin immunoprecipitation (ChIP) Journal of lipid research High 15961790
2007 HNF1α directly regulates miR-194 expression in intestinal epithelial cells; the 5′ conserved genomic region of the miR-194 parental gene contains an HNF1α-binding motif that is required for transcription and active in intestinal epithelial Caco-2 cells. Promoter-reporter assay, binding motif analysis, cell-line (Caco-2) transfection Nucleic acids symposium series Medium 18029763
2011 Tcf1 (HNF1α) directly activates the miR-192/194 cluster in liver, kidney, and small intestine; in Tcf1-/- mice the cluster is markedly down-regulated. miR-194 targets frizzled-6 (Fzd6) mRNA in vivo, identified by combining microarray analysis with Affymetrix profiling after miR-194 silencing or overexpression. miRNA microarray in Tcf1-/- mice, Affymetrix mRNA profiling, in vivo gain/loss of miR-194, luciferase reporter for Fzd6 targeting Hepatology High 21887698
2020 HNF1A physically recruits the histone demethylase KDM6A to genomic binding sites in pancreatic acinar cells; this remodels the acinar enhancer landscape (H3K27me3 removal), activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. Pancreas-specific Hnf1a-null transcriptomes phenocopy Kdm6a-null transcriptomes, and both defects synergize with KrasG12D to cause PDAC. Genetic mouse models (conditional KO, double mutant), ChIP-seq, ATAC-seq, RNA-seq, biochemical co-IP, tumor phenotyping The EMBO journal High 32154941
2021 MODY3 patient hiPSC-derived β-like cells carrying HNF1A+/H126D show reduced GLUT2 expression associated with decreased glucose uptake and ATP production; genome-wide ChIP-seq in endocrine progenitors identifies numerous HNF1A-occupied gene targets affected by the mutation, and molecular dynamics simulations predict that H126D compromises DNA binding. hiPSC differentiation, RNA-seq, ChIP-seq, glucose uptake assay, ATP measurement, molecular dynamics simulation Nature communications High 34035238
2022 The HASTER lncRNA promoter DNA (not the lncRNA itself) acts as a cis-regulatory element that maintains physiological HNF1A concentrations through positive and negative feedback loops; in pancreatic β cells, HASTER DNA modulates HNF1A promoter-enhancer interactions in cis. Loss of HASTER causes variegated HNF1A silencing or overexpression and hyperglycemia; excess HNF1A binds inappropriate genomic regions when the negative feedback is disrupted. Mouse Haster mutant models, human iPSC models, chromatin conformation (promoter-enhancer interaction), gene expression analysis, glucose tolerance testing Nature cell biology High 36202974
2022 An insulin hypersecretion phenotype precedes β-cell failure in MODY3 (HNF1A+/R272C) patient hiPSC-derived β cells; reduced KATP channel expression increases calcium signaling, causing more efficient membrane depolarization. Pharmacological targeting of ATP-sensitive K+ channels or low-voltage-activated Ca2+ channels rescues hypersecretion. Patient hiPSC-derived β cells, in vitro insulin secretion assay, in vivo transplantation into mice, pharmacological rescue with channel blockers, gene expression analysis Cell stem cell High 36563694
1996 In Xenopus embryos, the HNF1A promoter contains essential HNF1- and HNF4-binding sites; microinjection of HNF4 mRNA ectopically activates the endogenous HNF1A gene, and maternal HNF4 protein is present in an animal-to-vegetal gradient, indicating HNF4 initiates the transcriptional hierarchy leading to HNF1A expression. Xenopus microinjection, promoter mutational analysis, HNF1A promoter-reporter assay, detection of maternal HNF4 protein Mechanisms of development Medium 8808405
2000 The HNF1A gene promoter contains a DR1 retinoic acid response element that is bound by RXRα; RA increases HNF1A promoter activity in Hep3B cells, and RXRα overexpression further enhances this activity. Gel-shift assays confirm specific RXRα binding to the DR1 site. Transient transfection reporter assay, gel mobility shift assay (EMSA), RXRα overexpression Biochemical and biophysical research communications Medium 11027556
1997 HNF1α directly activates the rat UGT2B1 gene promoter through an HNF1-like element at −42 to −55 bp; deletion of this element abolishes basal activity and HNF1α-induced 50-fold induction. EMSA, DNase I footprinting, and supershift with HNF1α antisera confirm HNF1α binding in vitro and in liver nuclear extracts; HNF1β has no activating effect. Reporter gene (CAT) assay, EMSA, DNase I footprinting, supershift analysis, nuclear extract from rat liver DNA and cell biology High 9052741
2018 HNF1A depletion in pancreatic ductal adenocarcinoma cells reduces pancreatic cancer stem cell (PCSC) marker expression, impairs tumorsphere formation, causes apoptosis, and downregulates POU5F1/OCT4; HNF1A overexpression increases PCSC markers and drives tumor growth. In vivo, HNF1A depletion in xenografts impairs tumor growth and depletes PCSC marker-positive cells. siRNA knockdown, overexpression, tumorsphere formation assay, flow cytometry for PCSC markers, xenograft mouse model eLife High 30074477
2018 HNF1A positively regulates lncRNA CASC2 expression by directly binding an HNF1A-responsive element in the CASC2 gene, demonstrated by luciferase reporter assay; PTEN/Akt signaling is involved downstream of the HNF1A/CASC2 axis to control pancreatic cancer cell proliferation. Luciferase reporter assay, Western blot (Akt/PTEN phosphorylation), gene knockdown, proliferation assay Journal of cellular biochemistry Medium 28865121
2021 HNF1A knockdown in pancreatic cancer cell lines activates Akt and its downstream target mTOR, leading to increased S-phase entry and reduced apoptosis, and ~2-fold higher cell proliferation, consistent with a tumor-suppressor role mediated through Akt/mTOR pathway inhibition. siRNA knockdown, ATP proliferation assay, flow cytometry (cell cycle/apoptosis), Western blot for p-Akt and mTOR PloS one Medium 25793983
2003 HNF1α binds to a conserved site in the human prothrombin gene enhancer (site 2), and mutagenesis of this site reduces enhancer activity, establishing HNF1α as a direct transcriptional regulator of the prothrombin gene in hepatocytes. 5′-deletion reporter constructs, EMSA, site-directed mutagenesis, transient transfection in HepG2 and HuH7 cells Journal of thrombosis and haemostasis Medium 12911579

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 1280 30635237
2016 The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Science immunology 513 28018990
1991 vHNF1 is a homeoprotein that activates transcription and forms heterodimers with HNF1. The EMBO journal 275 1673926
2021 TCF1 in T cell immunity: a broadened frontier. Nature reviews. Immunology 191 34127847
2016 Tcf1 and Lef1 transcription factors establish CD8(+) T cell identity through intrinsic HDAC activity. Nature immunology 185 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 173 33139915
1991 Hepatic nuclear factor 1 (HNF1) shows a wider distribution than products of its known target genes in developing mouse. Development (Cambridge, England) 157 1685988
2007 The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes 150 18003757
1990 A distal dimerization domain is essential for DNA-binding by the atypical HNF1 homeodomain. Nucleic acids research 136 2216777
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
1998 Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 134 9562352
2022 Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop. Cancer cell 132 36423635
2018 Suppression of Tcf1 by Inflammatory Cytokines Facilitates Effector CD8 T Cell Differentiation. Cell reports 129 29466737
2021 Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 124 34534464
2015 TCF1 links GIPR signaling to the control of beta cell function and survival. Nature medicine 124 26642437
2000 Molecular targets of a human HNF1 alpha mutation responsible for pancreatic beta-cell dysfunction. The EMBO journal 113 10944108
2015 The Arabidopsis RCC1 Family Protein TCF1 Regulates Freezing Tolerance and Cold Acclimation through Modulating Lignin Biosynthesis. PLoS genetics 96 26393916
2019 TCF1 and LEF1 Control Treg Competitive Survival and Tfr Development to Prevent Autoimmune Diseases. Cell reports 94 31216480
1991 vHNF1 is expressed in epithelial cells of distinct embryonic origin during development and precedes HNF1 expression. Mechanisms of development 93 1685890
2022 In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue. The Journal of experimental medicine 92 35472220
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 87 33913198
2007 Distinct roles of HNF1beta, HNF1alpha, and HNF4alpha in regulating pancreas development, beta-cell function and growth. Endocrine development 87 17923767
1999 Anatomy of a homeoprotein revealed by the analysis of human MODY3 mutations. The Journal of biological chemistry 86 10585442
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 73 19924231
2022 TCF-1: a maverick in T cell development and function. Nature immunology 64 35487986
2023 Tumor immunogenicity dictates reliance on TCF1 in CD8+ T cells for response to immunotherapy. Cancer cell 62 37625402
2020 The Transcription Factor TCF1 in T Cell Differentiation and Aging. International journal of molecular sciences 62 32899486
2002 Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. The Journal of biological chemistry 62 11980910
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 60 37782797
2020 HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. The EMBO journal 60 32154941
2019 Novel insights into genetics and clinics of the HNF1A-MODY. Endocrine regulations 60 31517624
2014 From inception to output, Tcf1 and Lef1 safeguard development of T cells and innate immune cells. Immunologic research 59 24847765
2018 HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. eLife 58 30074477
2021 Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells. Nature communications 56 34035238
2012 MicroRNA-194 is a target of transcription factor 1 (Tcf1, HNF1α) in adult liver and controls expression of frizzled-6. Hepatology (Baltimore, Md.) 52 21887698
1993 Developmental regulation and tissue distribution of the liver transcription factor LFB1 (HNF1) in Xenopus laevis. Molecular and cellular biology 51 8417340
2022 Tcf1-CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis. Nature immunology 50 35882936
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
1994 Cloning and developmental expression of LFB3/HNF1 beta transcription factor in Xenopus laevis. Mechanisms of development 48 7524626
2015 Hepatocyte nuclear factor 1A (HNF1A) as a possible tumor suppressor in pancreatic cancer. PloS one 47 25793983
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 42 35328643
2018 HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. Journal of cellular biochemistry 41 28865121
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) 38 35970031
2020 Tcf1+ cells are required to maintain the inflationary T cell pool upon MCMV infection. Nature communications 38 32385253
2024 Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision. Immunity 37 38301652
2016 Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors. The Journal of biological chemistry 37 27044748
2013 Primary hepatocellular neoplasms in a MODY3 family with a novel HNF1A germline mutation. Journal of hepatology 36 23707370
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
2017 Wnt/Tcf1 pathway restricts embryonic stem cell cycle through activation of the Ink4/Arf locus. PLoS genetics 35 28346462
1997 The bifunctional protein DCoH modulates interactions of the homeodomain transcription factor HNF1 with nucleic acids. Journal of molecular biology 34 8995521
2024 Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy. Nature immunology 33 39327500
2022 The HASTER lncRNA promoter is a cis-acting transcriptional stabilizer of HNF1A. Nature cell biology 33 36202974
2007 Expression of HNF-4alpha (MODY1), HNF-1beta (MODY5), and HNF-1alpha (MODY3) proteins in the developing mouse pancreas. Gene expression patterns : GEP 33 17996499
2024 NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment. Cell reports 31 38451819
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
1993 The three-dimensional NMR-solution structure of the polypeptide fragment 195-286 of the LFB1/HNF1 transcription factor from rat liver comprises a nonclassical homeodomain. The EMBO journal 30 8491172
1991 Expression of liver type pyruvate kinase in insulinoma cells: involvement of LF-B1 (HNF1). Biochemical and biophysical research communications 30 1720308
2014 Treatment of young patients with HNF1A mutations (HNF1A-MODY). Diabetic medicine : a journal of the British Diabetic Association 29 25483937
2021 TCF-1 maintains CD8+ T cell stemness in tumor microenvironment. Journal of leukocyte biology 28 34047386
2007 Regulatory interaction of HNF1-alpha to microRNA-194 gene during intestinal epithelial cell differentiation. Nucleic acids symposium series (2004) 28 18029763
2005 Control of ACAT2 liver expression by HNF1. Journal of lipid research 28 15961790
2002 Evidence for haploinsufficiency of the human HNF1alpha gene revealed by functional characterization of MODY3-associated mutations. Biological chemistry 28 12530534
2021 The transcriptional repressor ID2 supports natural killer cell maturation by controlling TCF1 amplitude. The Journal of experimental medicine 27 33857289
2003 Functional characterization of transcription factor binding sites for HNF1-alpha, HNF3-beta (FOXA2), HNF4-alpha, Sp1 and Sp3 in the human prothrombin gene enhancer. Journal of thrombosis and haemostasis : JTH 27 12911579
2016 Structure-function studies of HNF1A (MODY3) gene mutations in South Indian patients with monogenic diabetes. Clinical genetics 26 26853433
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 23 24968817
2008 Role of Sp1 and HNF1 transcription factors in SGLT1 regulation during chronic intestinal inflammation. American journal of physiology. Gastrointestinal and liver physiology 23 18339704
2003 Tcf-1 expression during Xenopus development. Gene expression patterns : GEP 23 12711535
2000 Identification of retinoic acid-responsive elements on the HNF1alpha and HNF4alpha genes. Biochemical and biophysical research communications 23 11027556
2022 An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells. Cell stem cell 21 36563694
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
2010 Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report. Diabetes care 21 20705777
1997 HNF1 alpha activates the rat UDP glucuronosyltransferase UGT2B1 gene promoter. DNA and cell biology 21 9052741
2024 Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state. Immunity 20 39447575
2023 TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma. Science immunology 20 37801516
2015 Cell-autonomous requirement for TCF1 and LEF1 in the development of Natural Killer T cells. Molecular immunology 20 26490636
2008 Variant HNF1 modulates epithelial plasticity of normal and transformed ovary cells. Neoplasia (New York, N.Y.) 20 19048126
2005 Cystic kidney disease, chromophobe renal cell carcinoma and TCF2 (HNF1 beta) mutations. Nature clinical practice. Nephrology 20 16932376
2017 Knockdown of lncRNA HNF1A-AS1 inhibits oncogenic phenotypes in colorectal carcinoma. Molecular medicine reports 19 28791380
1991 Liver specific transcription factors of the HNF3-, C/EBP- and LFB1-families interact with the A-activator binding site. Nucleic acids research 19 1754374
2020 Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants. The Journal of clinical endocrinology and metabolism 18 32017842
2022 METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis. Human cell 17 36401086
2021 Tcf1 Sustains the Expression of Multiple Regulators in Promoting Early Natural Killer Cell Development. Frontiers in immunology 17 34917097
1997 The NMR solution structure of the non-classical homeodomain from the rat liver LFB1/HNF1 transcription factor. Journal of molecular biology 17 9126845
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
2004 Two distinct teleost hepatocyte nuclear factor 1 genes, hnf1alpha/tcf1 and hnf1beta/tcf2, abundantly expressed in liver, pancreas, gut and kidney of zebrafish. Gene 16 15302404
1995 Salmon HNF1: cDNA sequence, evolution, tissue specificity and binding to the salmon serum albumin promoter. Journal of molecular biology 16 7897653