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Target not currently curated in GtoImmuPdb
Target id: 608
Nomenclature: Hepatocyte nuclear factor-4-α
Systematic Nomenclature: NR2A1
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 474 | 20q13.12 | HNF4A | hepatocyte nuclear factor 4 alpha | 4,7 |
| Mouse | 474 | 2 84.32 cM | Hnf4a | hepatic nuclear factor 4, alpha | 5,19 |
| Rat | 474 | 3q42 | Hnf4a | hepatocyte nuclear factor 4, alpha | 20,54 |
| Previous and Unofficial Names |
| HNF4α | MODY1 | TCF14 | MODY | alpha transcription factor 4 | hepatocyte nuclear factor 4 alpha 3 | hepatocyte nuclear factor 4 alpha 9 | HNF4alpha10 | HNF4alpha11 | HNF4alpha12 | transcription factor 14 | transcription factor HNF-4 | Nuclear receptor 2A1 | hepatocyte nuclear factor 4 |
| Database Links |
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| Alphafold | P41235 (Hs), P49698 (Mm), P22449 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL5398 (Hs), CHEMBL3714705 (Rn) |
| Ensembl Gene | ENSG00000101076 (Hs), ENSMUSG00000017950 (Mm), ENSRNOG00000008895 (Rn) |
| Entrez Gene | 3172 (Hs), 15378 (Mm), 25735 (Rn) |
| Human Protein Atlas | ENSG00000101076 (Hs) |
| KEGG Gene | hsa:3172 (Hs), mmu:15378 (Mm), rno:25735 (Rn) |
| OMIM | 600281 (Hs) |
| Orphanet | ORPHA122455 (Hs) |
| Pharos | P41235 (Hs) |
| RefSeq Nucleotide | NM_000457 (Hs), NM_008261 (Mm), NM_022180 (Rn) |
| RefSeq Protein | NP_849180 (Hs), NP_032287 (Mm), NP_071516 (Rn) |
| UniProtKB | P41235 (Hs), P49698 (Mm), P22449 (Rn) |
| Wikipedia | HNF4A (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| linoleic acid |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Crystallographic studies showed that bacterially expressed HNF4α LBD binds a mixture of long chain fatty acids it a constitutive fashion. Another group reported similar results for the HNF4γ LBD. More recently, a collaboration between the Sladek and Forman groups showed that, in mammalian cells, HNF4α can exist in an unliganded form, as well as bind a natural fatty acid not found in bacteria [64]. | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists |
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| DNA Binding |
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| DNA Binding Comments | |||||||
| The rat HNF4α protein was purified and cDNA cloned based on its ability to bind regulatory elements in the mouse transthyretin (Ttr) and the human apolipoprotein CIII (APOC3) genes. These elements encompass what we now define as a divergent DR1 element. HNF4α can also bind DR2s but with lower affinity [23,55]. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| HIF | Physical, Functional | transactivation | 14,28,65 |
| Hepatocyte nuclear factor-4-α | Physical, Functional | transactivation | 22,28,49 |
| COUP-TFs | Functional | transactivation, competition for DNA binding | 27,37,56 |
| SHP | Physical, Functional | DNA binding, Transactivation | 31,52 |
| Smads | Physical, Functional | transactivation | 9,24 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| PPARGC1B | Co-activator | No | No | Yes | 33,62 | |
| GRIP1 | Co-activator | No | No | Yes | 53,60 | |
| CREBBP | Co-activator | No | No | Yes | CBP differentially activates HNF4 alpha splice variants in the F domain | 53,63 |
| CREBBP | Co-activator | No | No | Yes | SRC1 synergizes with p300 to further augment HNF4 alpha activity | 53,60 |
| PPARGC1A | Co-activator | No | No | Yes | PGC1 alpha is the most potent co-activator of HNF4 alpha found to date. PGC1 alpha and beta levels are normally low in the liver but increase upon fasting. | 33,62 |
| MED1 | Co-activator | No | No | Yes | Both the DBD and LBD of HNF4 alpha bind DRIP205. Polyamines decrease the binding of the DBD but increase the binding of the LBD to DRIP205. | 34-35 |
| NCOR2 | Co-repressor | No | No | Yes | Full repression by NCOR2/SMRT requires the F domain | 50 |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| APOC3 | Human | Activated | ChIP, Transient transfection, EMSA, Footprint | Three HNF4 alpha binding sites have been identified in the APOC3 promoter/enhancer region. The site closest to the promoter (-70/-82) was one of two sites used to purify HNF4 alpha protein initially. (This was also demonstrated in rodents and other species) | 25,41,55 |
| APOB | Human | Activated | ChIP, Transient transfection, EMSA, Footprint | HNF4 alpha synergizes with C/EBP alpha on the human ApoB promoter. | 36,41 |
| HNF1A | Human | Activated | ChIP, Transient transfection, EMSA | Mutations in the HNF4 alpha binding site in the HNF1A promoter result in MODY3. | 15,29,41 |
| PCK1 | Human | Activated | ChIP, Transient transfection, EMSA | HNF4 alpha is required for the glucocorticoid response of the PEPCK promoter. (shown in all species) | 17,41 |
| CYP3A4 | Human | Activated | Transient transfection, EMSA | HNF4 alpha regulates the expression of many CYP genes | 2,54,59 |
| Tissue Distribution Comments | |
| The two main isoforms from the P1 promoter (HNF4α 1 and 2) are expressed in the adult liver (hepatocytes), kidney and small intestine and colon but not the pancreas. HNF4α 3 and 4 were cloned from a human liver library. HNF4α 7 (and presumably 8) are expressed in the fetal liver and adult pancreas (beta cells) and to a lesser extent the adult liver (bile ducts), small intestine, colon and stomach. They are not found in the kidney. By in situ hybridization HNF4α has also been observed in the primary endoderm starting at E4.5 and in the liver, kidney, pancreas, stomach and intestine from E8.5 until birth. There is also a recent report of HNF4α from both the P1 and P2 promoter in the epididymis [10,55,57]. There is some controversy as to whether in human HNF4α 1 and 2 are also expressed in the adult pancreas (islet cells), in mouse they are not [12]. Methods used for these studies include: Northern, In situ, Westerns, Immunohistology and others. |
| Functional Assays
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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| Clinically-Relevant Mutations and Pathophysiology
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