HNF4A (hepatocyte nuclear factor 4-alpha, NR2A1) is an orphan nuclear receptor transcription factor expressed in liver, intestine, kidney and pancreatic islets. It binds DR1-type response elements in target promoters and enhancers as a homodimer and, through its fatty-acid-occupied ligand-binding domain and coactivator recruitment, constitutively activates transcription by RNA polymerase II. Its targets include apolipoprotein, bile-acid, gluconeogenic, drug-metabolism and coagulation-factor genes, making it a master regulator of hepatocyte differentiation and hepatic lipid and glucose metabolism; it also transrepresses CLOCK:BMAL1 to shape peripheral circadian rhythms. In beta cells it sustains the insulin-secretory gene program: heterozygous loss-of-function variants cause macrosomia with transient or persistent neonatal hyperinsulinaemic hypoglycaemia followed by maturity-onset diabetes of the young type 1 (MODY1), and a recurrent missense variant causes Fanconi renotubular syndrome with MODY. Multiple isoforms arise from two promoters (P1 and P2) and alternative splicing.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: Chromatin (ISA). Reason: HNF4A binds chromatin at target regulatory elements genome-wide; appropriate location for a DNA-binding TF. Supporting Evidence: PMID:30530698 We define a central role for HNF4A in maintaining cell-autonomous circadian |
| GO:0000976 transcription cis-regulatory region binding | IDA PMID:16488887 A Prospero-related homeodomain protein is a novel co-regulat... | ACCEPT | Summary: Transcription cis-regulatory region binding. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0000976 transcription cis-regulatory region binding | IEA GO_REF:0000107 | ACCEPT | Summary: Transcription cis-regulatory region binding. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: RNA polymerase II cis-regulatory region sequence-specific DNA binding. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: DNA-binding transcription factor activity, RNA polymerase II-specific. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: DNA-binding transcription activator activity, RNA polymerase II-specific. Reason: HNF4A predominantly activates its targets (apolipoproteins, CYP7A1, PEPCK, hepatic and beta-cell genes) by recruiting coactivators and RNA polymerase II. Supporting Evidence: PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the |
| GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: DNA-binding transcription activator activity, RNA polymerase II-specific. Reason: HNF4A predominantly activates its targets (apolipoproteins, CYP7A1, PEPCK, hepatic and beta-cell genes) by recruiting coactivators and RNA polymerase II. Supporting Evidence: PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the |
| GO:0003677 DNA binding | IDA PMID:10551874 Mitogen-activated protein kinase regulates transcription of ... | ACCEPT | Summary: DNA binding (IDA, EMSA on apolipoprotein promoters). Reason: Correct; HNF4A binds nuclear hormone receptor response elements. Less specific than the sequence-specific terms. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified PMID:7615825 which binds to the NHRRE, |
| GO:0003677 DNA binding | IDA PMID:7615825 Intestinal apolipoprotein AI gene transcription is regulated... | ACCEPT | Summary: DNA binding (IDA, EMSA on apolipoprotein promoters). Reason: Correct; HNF4A binds nuclear hormone receptor response elements. Less specific than the sequence-specific terms. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified PMID:7615825 which binds to the NHRRE, |
| GO:0003677 DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: DNA binding (IDA, EMSA on apolipoprotein promoters). Reason: Correct; HNF4A binds nuclear hormone receptor response elements. Less specific than the sequence-specific terms. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified PMID:7615825 which binds to the NHRRE, |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Chromatin binding (electronic). Reason: HNF4A occupies chromatin at thousands of sites; acceptable general term. Supporting Evidence: PMID:30530698 We define a central role for HNF4A in maintaining cell-autonomous circadian |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10330009 Regulation of alpha1-antitrypsin gene expression in human in... | ACCEPT | Summary: DNA-binding transcription factor activity. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:12911579 Functional characterization of transcription factor binding ... | ACCEPT | Summary: DNA-binding transcription factor activity. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:16488887 A Prospero-related homeodomain protein is a novel co-regulat... | ACCEPT | Summary: DNA-binding transcription factor activity. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:7615825 Intestinal apolipoprotein AI gene transcription is regulated... | ACCEPT | Summary: DNA-binding transcription factor activity. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: DNA-binding transcription factor activity. Reason: HNF4A is a sequence-specific DNA-binding nuclear receptor transcription factor that binds direct-repeat (DR1-type) response elements in target promoters and recruits RNA polymerase II; this is its core activity. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of PMID:7615825 which binds to the NHRRE, |
| GO:0004879 nuclear receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear receptor activity. Reason: HNF4A is an orphan member of the nuclear receptor superfamily (NR2A1) whose ligand-binding domain constitutively binds fatty acids; the nuclear receptor term is the most precise MF. Supporting Evidence: PMID:12193589 fatty acids are endogenous ligands for HNF4 alpha PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds |
| GO:0004879 nuclear receptor activity | IDA PMID:12193589 Crystal structure of the HNF4 alpha ligand binding domain in... | ACCEPT | Summary: Nuclear receptor activity. Reason: HNF4A is an orphan member of the nuclear receptor superfamily (NR2A1) whose ligand-binding domain constitutively binds fatty acids; the nuclear receptor term is the most precise MF. Supporting Evidence: PMID:12193589 fatty acids are endogenous ligands for HNF4 alpha PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds |
| GO:0005102 signaling receptor binding | IDA PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that c... | MODIFY | Summary: Signaling receptor binding (IDA, HNF4 LBD study). Reason: The cited experiment shows the HNF4 ligand-binding domain interacting with nuclear receptor coactivators, which is transcription coactivator binding, not binding to a signalling receptor. Proposed replacements: transcription coactivator binding Supporting Evidence: PMID:12220494 The purified HNF4 LBDs interacted with nuclear receptor |
| GO:0005504 fatty acid binding | IDA PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that c... | KEEP AS NON CORE | Summary: Fatty acid binding (IDA). Reason: The HNF4 LBD carries tightly bound C14-C18 fatty acids that do not readily exchange; a structural ligand-binding property supporting its constitutive nuclear receptor activity. Supporting Evidence: PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds file:human/HNF4A/HNF4A-uniprot.txt MISCELLANEOUS: Binds fatty acids. |
| GO:0005515 protein binding | IPI PMID:12855700 Sterol regulatory element-binding protein-2 interacts with h... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:16488887 A Prospero-related homeodomain protein is a novel co-regulat... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:17932483 Cited2, a coactivator of HNF4alpha, is essential for liver d... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:17978169 Dexamethasone-mediated up-regulation of human CYP2A6 involve... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:19549071 Functional dissection of the alpha-synuclein promoter: trans... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:19846556 Multiple binding modes between HNF4alpha and the LXXLL motif... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:21532585 PKA-dependent regulation of the histone lysine demethylase c... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:23714182 Transcription of the human microsomal epoxide hydrolase gene... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:23714368 FOXO6 promotes gastric cancer cell tumorigenicity via upregu... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:28128295 RNA helicase DDX3 maintains lipid homeostasis through upregu... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005515 protein binding | IPI PMID:35140242 Human transcription factor protein interaction networks. | REMOVE | Summary: Protein binding (IPI) with co-regulators and other partners (e.g. PROX1, NR0B2, CLOCK/BMAL1, interactome screens). Reason: Uninformative term. Functionally relevant partners act as transcription co-regulators, which are better captured by coregulator-binding or regulation-of-transcription terms; removing protein binding does not imply the interactions are false. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nucleus. Reason: HNF4A acts in the nucleus as a transcription factor. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. PMID:14563941 expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus |
| GO:0005634 nucleus | IDA PMID:14563941 A crucial role of hepatocyte nuclear factor-4 expression in ... | ACCEPT | Summary: Nucleus. Reason: HNF4A acts in the nucleus as a transcription factor. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. PMID:14563941 expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus |
| GO:0005634 nucleus | IDA PMID:15574752 Role of a BCL9-related beta-catenin-binding protein, B9L, in... | ACCEPT | Summary: Nucleus. Reason: HNF4A acts in the nucleus as a transcription factor. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. PMID:14563941 expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus |
| GO:0005634 nucleus | IDA PMID:7615825 Intestinal apolipoprotein AI gene transcription is regulated... | ACCEPT | Summary: Nucleus. Reason: HNF4A acts in the nucleus as a transcription factor. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. PMID:14563941 expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nucleus. Reason: HNF4A acts in the nucleus as a transcription factor. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. PMID:14563941 expressed HNF-1, HNF-4alpha, HNF-3beta, and C/EBPalpha in the nucleus |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm. Reason: Correct nuclear sub-location for a TF. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-376419 | ACCEPT | Summary: Nucleoplasm. Reason: Correct nuclear sub-location for a TF. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-382096 | ACCEPT | Summary: Nucleoplasm. Reason: Correct nuclear sub-location for a TF. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt SUBCELLULAR LOCATION: Nucleus. |
| GO:0005737 cytoplasm | IDA PMID:14563941 A crucial role of hepatocyte nuclear factor-4 expression in ... | KEEP AS NON CORE | Summary: Cytoplasm (IDA, human liver immunostaining). Reason: Cytoplasmic HNF4A staining was seen in residual hepatocytes of necrotic liver; a regulated/pathological pool rather than its site of action. Supporting Evidence: PMID:14563941 whereas residual hepatocytes in massive |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Regulation of DNA-templated transcription. Reason: Correct general process. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Transcriptional regulator which controls the expression of |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:10330009 Regulation of alpha1-antitrypsin gene expression in human in... | ACCEPT | Summary: Regulation of transcription by RNA polymerase II. Reason: Core process. Supporting Evidence: PMID:10330009 HNF-1alpha and HNF-4 had a synergistic effect on alpha1-AT gene expression file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the |
| GO:0006357 regulation of transcription by RNA polymerase II | IDA PMID:12911579 Functional characterization of transcription factor binding ... | ACCEPT | Summary: Regulation of transcription by RNA polymerase II. Reason: Core process. Supporting Evidence: PMID:10330009 HNF-1alpha and HNF-4 had a synergistic effect on alpha1-AT gene expression file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:18163890 HNF4 alpha orchestrates a set of 14 genes to down-regulate c... | ACCEPT | Summary: Regulation of transcription by RNA polymerase II. Reason: Core process. Supporting Evidence: PMID:10330009 HNF-1alpha and HNF-4 had a synergistic effect on alpha1-AT gene expression file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the |
| GO:0006805 xenobiotic metabolic process | IMP PMID:17827783 Role of human hepatocyte nuclear factor 4alpha in the expres... | KEEP AS NON CORE | Summary: Xenobiotic metabolic process (acts upstream, siRNA in hepatocytes). Reason: HNF4A drives expression of drug-metabolising CYPs, UGTs and transporters; it acts upstream as a TF, not as a metabolic enzyme. Supporting Evidence: PMID:17827783 plays a dominant role in the expression of drug-metabolizing enzymes and |
| GO:0007596 blood coagulation | IDA PMID:12911579 Functional characterization of transcription factor binding ... | KEEP AS NON CORE | Summary: Blood coagulation (acts upstream, prothrombin enhancer). Reason: HNF4A binds the prothrombin enhancer; regulation of a coagulation-factor gene is an indirect, upstream contribution. Supporting Evidence: PMID:12911579 We identified six different TFs binding to three |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc ion binding (InterPro). Reason: Structural zinc in the nuclear-receptor DNA-binding domain zinc fingers; supports DNA binding but is not a function in itself. Supporting Evidence: PMID:7615825 which binds to the NHRRE, |
| GO:0008285 negative regulation of cell population proliferation | IMP PMID:18163890 HNF4 alpha orchestrates a set of 14 genes to down-regulate c... | KEEP AS NON CORE | Summary: Negative regulation of cell population proliferation (IMP, HEK293). Reason: Induced HNF4A represses proliferation of HEK293 cells via a set of target genes; a downstream consequence of its TF activity. Supporting Evidence: PMID:18163890 HNF4 alpha orchestrates a set of 14 genes to down-regulate cell proliferation |
| GO:0009749 response to glucose | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to glucose (electronic/ISS). Reason: Rodent-derived; HNF4A participates in glucose-responsive gene regulation in liver and beta cells. Non-core. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt years of age), a primary defect in insulin secretion and frequent |
| GO:0009749 response to glucose | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Response to glucose (electronic/ISS). Reason: Rodent-derived; HNF4A participates in glucose-responsive gene regulation in liver and beta cells. Non-core. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt years of age), a primary defect in insulin secretion and frequent |
| GO:0019216 regulation of lipid metabolic process | IDA PMID:10551874 Mitogen-activated protein kinase regulates transcription of ... | KEEP AS NON CORE | Summary: Regulation of lipid metabolic process (IDA, apoCIII promoter). Reason: HNF4A regulates apolipoprotein genes and thereby lipid metabolism; a downstream physiological role of its TF activity. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell differentiation (IBA). Reason: HNF4A is required for hepatocyte specification from endoderm and maintenance of differentiated epithelial phenotypes; non-core developmental role. Supporting Evidence: PMID:30597922 HNF4A Regulates the Formation of Hepatic Progenitor Cells from Human |
| GO:0030308 negative regulation of cell growth | IMP PMID:18163890 HNF4 alpha orchestrates a set of 14 genes to down-regulate c... | KEEP AS NON CORE | Summary: Negative regulation of cell growth (IMP, HEK293). Reason: As above; indirect via target genes. Supporting Evidence: PMID:18163890 HNF4 alpha orchestrates a set of 14 genes to down-regulate cell proliferation |
| GO:0030522 intracellular receptor signaling pathway | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Intracellular receptor signaling pathway (inferred from nuclear receptor activity). Reason: Generic inference from nuclear receptor activity; HNF4A is constitutively active and not classically ligand-triggered, so not core. Supporting Evidence: PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds |
| GO:0042593 glucose homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glucose homeostasis. Reason: HNF4A loss causes MODY1 and, in neonates, hyperinsulinaemic hypoglycaemia; it acts upstream via transcription of beta-cell and hepatic metabolic genes. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt years of age), a primary defect in insulin secretion and frequent PMID:17407387 Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth |
| GO:0042593 glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Glucose homeostasis. Reason: HNF4A loss causes MODY1 and, in neonates, hyperinsulinaemic hypoglycaemia; it acts upstream via transcription of beta-cell and hepatic metabolic genes. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt years of age), a primary defect in insulin secretion and frequent PMID:17407387 Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cholesterol homeostasis. Reason: Downstream physiological consequence of HNF4A regulation of hepatic lipid/bile-acid genes (e.g. CYP7A1). Supporting Evidence: PMID:16488887 an important |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cholesterol homeostasis. Reason: Downstream physiological consequence of HNF4A regulation of hepatic lipid/bile-acid genes (e.g. CYP7A1). Supporting Evidence: PMID:16488887 an important |
| GO:0042752 regulation of circadian rhythm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of circadian rhythm. Reason: HNF4A transrepresses CLOCK:BMAL1 and maintains cell-autonomous oscillations in liver and colon cells. Supporting Evidence: PMID:30530698 We define a central role for HNF4A in maintaining cell-autonomous circadian |
| GO:0042752 regulation of circadian rhythm | IMP PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | KEEP AS NON CORE | Summary: Regulation of circadian rhythm. Reason: HNF4A transrepresses CLOCK:BMAL1 and maintains cell-autonomous oscillations in liver and colon cells. Supporting Evidence: PMID:30530698 We define a central role for HNF4A in maintaining cell-autonomous circadian |
| GO:0042803 protein homodimerization activity | IDA PMID:12220494 Hepatocyte nuclear factor 4 is a transcription factor that c... | KEEP AS NON CORE | Summary: Protein homodimerization activity (IDA). Reason: HNF4A binds DNA as a homodimer; a structural prerequisite of DNA binding rather than its function. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt Homodimerization is required for HNF4-alpha to bind to its |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Sequence-specific DNA binding. Reason: Correct. Supporting Evidence: PMID:7615825 which binds to the NHRRE, |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:30530698 Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modula... | KEEP AS NON CORE | Summary: Negative regulation of DNA-templated transcription (IDA, CLOCK:BMAL1 transrepression). Reason: HNF4A transrepresses CLOCK:BMAL1 activity; real but a secondary, context-specific function. Supporting Evidence: PMID:30530698 Here we show that the nuclear receptor HNF4A strongly file:human/HNF4A/HNF4A-uniprot.txt Represses the CLOCK-BMAL1 |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:16488887 A Prospero-related homeodomain protein is a novel co-regulat... | ACCEPT | Summary: Positive regulation of DNA-templated transcription. Reason: Core process; HNF4A activates target genes. Supporting Evidence: PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000117 | ACCEPT | Summary: Positive regulation of DNA-templated transcription. Reason: Core process; HNF4A activates target genes. Supporting Evidence: PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Positive regulation of transcription by RNA polymerase II. Reason: Core process; HNF4A recruits RNA polymerase II to target promoters. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:7615825 Intestinal apolipoprotein AI gene transcription is regulated... | ACCEPT | Summary: Positive regulation of transcription by RNA polymerase II. Reason: Core process; HNF4A recruits RNA polymerase II to target promoters. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:17827783 Role of human hepatocyte nuclear factor 4alpha in the expres... | ACCEPT | Summary: Positive regulation of transcription by RNA polymerase II. Reason: Core process; HNF4A recruits RNA polymerase II to target promoters. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:30597922 HNF4A Regulates the Formation of Hepatic Progenitor Cells fr... | ACCEPT | Summary: Positive regulation of transcription by RNA polymerase II. Reason: Core process; HNF4A recruits RNA polymerase II to target promoters. Supporting Evidence: file:human/HNF4A/HNF4A-uniprot.txt progenitor cells, facilitating the recruitment of RNA pol II to the PMID:7615825 dramatically stimulates apoAI gene expression in Caco-2 cells but not in HepG2 |
| GO:0050796 regulation of insulin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of insulin secretion. Reason: Beta-cell Hnf4a deletion causes fetal hyperinsulinaemia and neonatal hyperinsulinaemic hypoglycaemia, and human heterozygous variants cause neonatal hyperinsulinism followed by MODY1. HNF4A affects secretion indirectly as a transcriptional regulator of the beta-cell program. Supporting Evidence: PMID:17407387 Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth file:human/HNF4A/HNF4A-uniprot.txt characterized by Fanconi syndrome associated with a beta cell phenotype |
| GO:0050796 regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of insulin secretion. Reason: Beta-cell Hnf4a deletion causes fetal hyperinsulinaemia and neonatal hyperinsulinaemic hypoglycaemia, and human heterozygous variants cause neonatal hyperinsulinism followed by MODY1. HNF4A affects secretion indirectly as a transcriptional regulator of the beta-cell program. Supporting Evidence: PMID:17407387 Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth file:human/HNF4A/HNF4A-uniprot.txt characterized by Fanconi syndrome associated with a beta cell phenotype |
| GO:0055088 lipid homeostasis | IMP PMID:17827783 Role of human hepatocyte nuclear factor 4alpha in the expres... | KEEP AS NON CORE | Summary: Lipid homeostasis (acts upstream, siRNA). Reason: Indirect via target-gene regulation. Supporting Evidence: PMID:17827783 plays a dominant role in the expression of drug-metabolizing enzymes and |
| GO:0055091 phospholipid homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Phospholipid homeostasis. Reason: Downstream of hepatic lipid gene regulation; non-core. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified |
| GO:0055091 phospholipid homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Phospholipid homeostasis. Reason: Downstream of hepatic lipid gene regulation; non-core. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RNA polymerase II-specific DNA-binding transcription factor binding. Reason: HNF4A cooperates with other liver-enriched TFs (e.g. HNF1A synergy on target promoters); real but secondary. Supporting Evidence: PMID:10330009 HNF-1alpha and HNF-4 had a synergistic effect on alpha1-AT gene expression |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: RNA polymerase II-specific DNA-binding transcription factor binding. Reason: HNF4A cooperates with other liver-enriched TFs (e.g. HNF1A synergy on target promoters); real but secondary. Supporting Evidence: PMID:10330009 HNF-1alpha and HNF-4 had a synergistic effect on alpha1-AT gene expression |
| GO:0070328 triglyceride homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Triglyceride homeostasis. Reason: HNF4A regulates apoCIII and other triglyceride-relevant genes; indirect. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified |
| GO:0070328 triglyceride homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Triglyceride homeostasis. Reason: HNF4A regulates apoCIII and other triglyceride-relevant genes; indirect. Supporting Evidence: PMID:10551874 The major protein binding to this site was identified |
| GO:1903268 positive regulation of ornithine catabolic process | IMP PMID:17827783 Role of human hepatocyte nuclear factor 4alpha in the expres... | MARK AS OVER ANNOTATED | Summary: Positive regulation of ornithine catabolic process (IMP, hepatocyte siRNA). Reason: Derived from target-gene expression changes after HNF4A knockdown; HNF4A regulates hundreds of hepatic metabolic genes, and annotating each downstream metabolic process over-annotates a general transcription factor. Supporting Evidence: PMID:17827783 plays a dominant role in the expression of drug-metabolizing enzymes and |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: Sequence-specific double-stranded DNA binding (methyl-SELEX). Reason: HNF4A motif specificity was profiled by SELEX; consistent with its core DNA-binding activity. Supporting Evidence: PMID:28473536 Impact of cytosine methylation on DNA binding specificities of human |
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Download this section (compressed HTML)Q: Which beta-cell HNF4A target genes explain the switch from fetal/neonatal hyperinsulinism to later insulin-secretory failure in HNF4A haploinsufficiency?
Experiment: Profile HNF4A occupancy (CUT&RUN) and transcriptome in human stem-cell-derived beta cells heterozygous for HNF4A loss at fetal-like and matured stages, together with glucose-stimulated insulin secretion, to identify the targets driving early hypersecretion versus later failure.
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