Nomenclature: Hepatocyte nuclear factor-4-α

Systematic Nomenclature: NR2A1

Family: 2A. Hepatocyte nuclear factor-4 receptors

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
Species AA Chromosomal Location Gene Symbol Gene Name Reference
Human 464 20q12-q13.1 HNF4A hepatocyte nuclear factor 4, alpha 4,7
Mouse 474 2H3 Hnf4a hepatic nuclear factor 4, alpha 5,18
Rat 465 3q42 Hnf4a hepatocyte nuclear factor 4, alpha 19,49
Previous and Unofficial Names
HNF4
HNF4α
Hepatocyte nuclear factor 4-α
MODY1
TCF14
MODY
NR2A1
Hnf4alpha
Tcf4
HNF-4-alpha
HNF4alpha10
HNF4alpha11
HNF4alpha12
TCF-14
alpha transcription factor 4
hepatic nuclear factor 4
hepatic nuclear factor 4 (alpha transcription factor 4)
hepatic nuclear factor 4, alpha
hepatocyte nuclear factor 4 alpha 3
hepatocyte nuclear factor 4 alpha 9
hepatocyte nuclear factor 4, alpha
hepatocyte nuclear factor 4-alpha
nuclear receptor subfamily 2 group A member 1
transcription factor 14
transcription factor HNF-4
HNF-4
HNF4 alpha
Nuclear receptor 2A1
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
NURSA Receptor
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  HNF4a Ligand Binding Domain
PDB Id:  3FS1
Resolution:  2.2Å
Species:  Human
References:  43
Natural/Endogenous Ligands
Comments: Orphan
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
linoleic acid Hs Full agonist - - 58
[58]
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 [58].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
BI6015 Hs Antagonist - - 25
[25]
DNA Binding
Structure:  Homodimer
HRE core sequence:  AGGTCA n AGGTCA
Response element:  DR1, DR2
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 [22,50].
Co-binding Partners
Name Interaction Effect Reference
HIF Physical, Functional transactivation 13,27,59
Hepatocyte nuclear factor-4-α Physical, Functional transactivation 21,27,44
COUP-TFs Functional transactivation, competition for DNA binding 26,34,51
SHP Physical, Functional DNA binding, Transactivation 29,47
Smads Physical, Functional transactivation 9,23
Main Co-regulators
Name Activity Specific Ligand dependent AF-2 dependent Comments References
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. 30,56
CREBBP Co-activator No No Yes CBP differentially activates HNF4 alpha splice variants in the F domain 48,57
CREBBP Co-activator No No Yes SRC1 synergizes with p300 to further augment HNF4 alpha activity 48,55
PPARGC1B Co-activator No No Yes 30,56
GRIP1 Co-activator No No Yes 48,55
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. 31-32
NCOR2 Co-repressor No No Yes Full repression by NCOR2/SMRT requires the F domain 45
Main Target Genes
Name Species Effect Technique Comments References
CYP3A4 Human Activated Transient transfection, EMSA HNF4 alpha regulates the expression of many CYP genes 2,49,54
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) 24,37,50
APOB Human Activated ChIP, Transient transfection, EMSA, Footprint HNF4 alpha synergizes with C/EBP alpha on the human ApoB promoter. 33,37
HNF1A Human Activated ChIP, Transient transfection, EMSA Mutations in the HNF4 alpha binding site in the HNF1A promoter result in MODY3. 14,28,37
PCK1 Human Activated ChIP, Transient transfection, EMSA HNF4 alpha is required for the glucocorticoid response of the PEPCK promoter. (shown in all species) 16,37
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 [10,50,52]. 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
Ectopic over expression
Species:  Mouse
Tissue:  Fibroblasts
Response measured:  Ectopic over expression of HNF4 alpha in fibroblasts induces a mesenchymal-to-epithelial transition, indicating that HNF4 alpha is a dominant regulator of the epithelial phenotype.
References:  40
Physiological Consequences of Altering Gene Expression
HNF4 alpha Null Mice: Targeted disruption of the HNF4 alpha gene results in embryonic lethality; at E7.5 the embryos are clearly abnormal and at E9.5 they die. The embryos initiate but do not complete gastrulation in the absence of HNF4 alpha. HNF4 alpha also regulates extra embryonic endoderm function as well as hepatocyte differentiation.
Species:  Mouse
Tissue: 
Technique:  Knockout mice and tetraploid embryo complementation
References:  8,11
Hepatocyte-specific knock-out: Adult mice lacking hepatic HNF4 alpha expression accumulated lipid in the liver and exhibited greatly reduced serum cholesterol and triglyceride levels and increased serum bile acid concentrations. Embryonic HNF4 alpha is required for morphological and functional differentiation of hepatocytes, accumulation of hepatic glycogen stores and generation of a hepatic epithelium.
Species:  Mouse
Tissue:  Hepatocytes
Technique:  Liver-specific knockout with Alb-Cre or AlbAFP-Cre
References:  20,39-40
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Hnf4atm1.1Gonz|Tg(Ins2-cre)25Mgn Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Ins2-cre)25Mgn/0
involves: 129X1/SvJ * C57BL/6 * DBA
MGI:109128  MGI:2176225  MP:0003484 abnormal channel response PMID: 16377800 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0001675 abnormal ectoderm development PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0001672 abnormal embryogenesis/ development PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0002085 abnormal embryonic tissue morphology PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0002086 abnormal extraembryonic tissue morphology PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0001695 abnormal gastrulation PMID: 7958910 
Hnf4atm1Sad|Tg(Alb1-cre)1Khk Hnf4atm1Sad/Hnf4atm1Sad,Tg(Alb1-cre)1Khk/0
Not Specified
MGI:109128  MGI:2661922  MP:0000607 abnormal hepatocyte morphology PMID: 12808453 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0000607 abnormal hepatocyte morphology PMID: 11158324 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0002118 abnormal lipid homeostasis PMID: 16498401 
Hnf4atm1Sad|Tg(Alb1-cre)1Khk Hnf4atm1Sad/Hnf4atm1Sad,Tg(Alb1-cre)1Khk/0
Not Specified
MGI:109128  MGI:2661922  MP:0000596 abnormal liver development PMID: 12808453 
Hnf4atm1Sad|Tg(Alb1-cre)1Khk Hnf4atm1Sad/Hnf4atm1Sad,Tg(Alb1-cre)1Khk/0
Not Specified
MGI:109128  MGI:2661922  MP:0000598 abnormal liver morphology PMID: 12808453 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0000598 abnormal liver morphology PMID: 11158324 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0002230 abnormal primitive streak formation PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0001718 abnormal yolk sac morphology PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0003087 absent allantois PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0005030 absent amnion PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0009593 absent chorion PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0001683 absent mesoderm PMID: 7958910 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0005179 decreased circulating cholesterol level PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0005179 decreased circulating cholesterol level PMID: 11158324 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0002702 decreased circulating free fatty acid level PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0000186 decreased circulating HDL cholesterol level PMID: 11158324 
Hnf4atm1.1Gonz|Tg(Ins2-cre)25Mgn Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Ins2-cre)25Mgn/0
involves: 129X1/SvJ * C57BL/6 * DBA
MGI:109128  MGI:2176225  MP:0002727 decreased circulating insulin level PMID: 16377800 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0002644 decreased circulating triglyceride level PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0002644 decreased circulating triglyceride level PMID: 11158324 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
involves: 129S4/SvJae * C57BL/6
MGI:109128  MP:0001698 decreased embryo size PMID: 9825865 
Hnf4atm1Sad|Tg(Alb1-cre)1Khk Hnf4atm1Sad/Hnf4atm1Sad,Tg(Alb1-cre)1Khk/0
Not Specified
MGI:109128  MGI:2661922  MP:0005439 decreased glycogen level PMID: 12808453 
Hnf4atm1Sad|Tg(Alb1-cre)1Khk Hnf4atm1Sad/Hnf4atm1Sad,Tg(Alb1-cre)1Khk/0
Not Specified
MGI:109128  MGI:2661922  MP:0000608 dissociated hepatocytes PMID: 12808453 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0003984 embryonic growth retardation PMID: 7958910 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0006207 embryonic lethality during organogenesis PMID: 7958910 
Hnf4atm2Mwei Hnf4atm2Mwei/Hnf4atm2Mwei
involves: 129S2/SvPas * C57BL/6
MGI:109128  MP:0006207 embryonic lethality during organogenesis PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0000599 enlarged liver PMID: 11158324 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0002628 hepatic steatosis PMID: 16498401 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0004151 hypoferremia PMID: 16498401 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0004119 hypokalemia PMID: 16498401 
Hnf4atm1.1Mwei Hnf4atm1.1Mwei/Hnf4atm1.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0005293 impaired glucose tolerance PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Ins2-cre)25Mgn Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Ins2-cre)25Mgn/0
involves: 129X1/SvJ * C57BL/6 * DBA
MGI:109128  MGI:2176225  MP:0005293 impaired glucose tolerance PMID: 16377800 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
involves: 129S4/SvJae * C57BL/6
MGI:109128  MP:0006042 increased apoptosis PMID: 9825865 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0005344 increased circulating bilirubin level PMID: 16498401 
Hnf4atm2.1Mwei Hnf4atm2.1Mwei/Hnf4atm2.1Mwei
involves: 129S2/SvPas * BALB/c * C57BL/6
MGI:109128  MP:0002575 increased circulating ketone body level PMID: 16498401 
Hnf4atm1Dnl Hnf4atm1Dnl/Hnf4atm1Dnl
either: (involves: 129S4/SvJae) or (involves: 129S4/SvJae * C57BL/6)
MGI:109128  MP:0003895 increased ectoderm apoptosis PMID: 7958910 
Hnf4atm1Sad Hnf4atm1Sad/Hnf4atm1Sad
involves: 129S1/Sv * 129X1/SvJ * CD-1
MGI:109128  MP:0002169 no abnormal phenotype detected PMID: 11857799 
Hnf4a+|Hnf4atm1(cre)Sdv Hnf4atm1(cre)Sdv/Hnf4a+
involves: 129S/SvEv * CD-1
MGI:109128  MP:0002169 no abnormal phenotype detected PMID: 15282747 
Hnf4atm1Mwei Hnf4atm1Mwei/Hnf4atm1Mwei
involves: 129S2/SvPas * C57BL/6
MGI:109128  MP:0002169 no abnormal phenotype detected PMID: 16498401 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0002083 premature death PMID: 11158324 
Hnf4atm1Gonz Hnf4atm1Gonz/Hnf4atm1Gonz
involves: 129X1/SvJ
MGI:109128  MP:0002080 prenatal lethality PMID: 11158324 
Hnf4atm1.2Gonz Hnf4atm1.2Gonz/Hnf4atm1.2Gonz
involves: 129X1/SvJ * FVB/N
MGI:109128  MP:0002080 prenatal lethality PMID: 11158324 
Hnf4atm1.1Gonz|Tg(Alb1-cre)1Dlr Hnf4atm1.1Gonz/Hnf4atm1.1Gonz,Tg(Alb1-cre)1Dlr/0
involves: 129X1/SvJ * FVB/N
MGI:109128  MGI:2176944  MP:0001263 weight loss PMID: 11158324 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Factor VII deficiency
OMIM:  227500
Role: 
References:  3
Mutations not determined
Disease:  Type 2 diabetes [early-onset]
OMIM:  600281
Comments: 
References:  1
Click column headers to sort
Type Species Molecular location Description Reference
nonsynonymous point mutation Human asp126tyr; asp126his; arg154gln 1
Disease:  Type 2 diabetes [late-onset]
OMIM:  125853
Comments: 
References:  15,17,36,41
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human LBD (arg323his), F domain (val393ile)
Disease:  Maturity-onset diabetes of the young, Type 1; (MODY1)
OMIM:  125850, 606391
Orphanet:  552
Comments: 
References:  6,35,38,42,46,53
Mutations not determined
Disease:  Hyperinsulinism due to HNF4A deficiency
Orphanet:  263455
References: 
Mutations not determined

REFERENCES

1. Aguilar-Salinas CA, Reyes-Rodríguez E, Ordóñez-Sánchez ML, Torres MA, Ramírez-Jiménez S, Domínguez-López A, Martínez-Francois JR, Velasco-Pérez ML, Alpizar M, García-García E, Gómez-Pérez F, Rull J, Tusié-Luna MT. (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population. J. Clin. Endocrinol. Metab.86 (1): 220-6. [PMID:11232004]

2. Akiyama TE, Gonzalez FJ. (2003) Regulation of P450 genes by liver-enriched transcription factors and nuclear receptors. Biochim. Biophys. Acta1619 (3): 223-34. [PMID:12573481]

3. Arbini AA, Pollak ES, Bayleran JK, High KA, Bauer KA. (1997) Severe factor VII deficiency due to a mutation disrupting a hepatocyte nuclear factor 4 binding site in the factor VII promoter. Blood89 (1): 176-82. [PMID:8978290]

4. Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK. (1997) Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17. Hum. Genet.99 (2): 233-6. [PMID:9048927]

5. Avraham KB, Prezioso VR, Chen WS, Lai E, Sladek FM, Zhong W, Darnell JE, Jenkins NA, Copeland NG. (1992) Murine chromosomal location of four hepatocyte-enriched transcription factors: HNF-3 alpha, HNF-3 beta, HNF-3 gamma, and HNF-4. Genomics13 (2): 264-8. [PMID:1612587]

6. Barrio R, Bellanné-Chantelot C, Moreno JC, Morel V, Calle H, Alonso M, Mustieles C. (2002) Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J. Clin. Endocrinol. Metab.87 (6): 2532-9. [PMID:12050210]

7. Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B. (1994) Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene147 (2): 269-72. [PMID:7926813]

8. Chen WS, Manova K, Weinstein DC, Duncan SA, Plump AS, Prezioso VR, Bachvarova RF, Darnell JE. (1994) Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev.8 (20): 2466-77. [PMID:7958910]

9. Chou WC, Prokova V, Shiraishi K, Valcourt U, Moustakas A, Hadzopoulou-Cladaras M, Zannis VI, Kardassis D. (2003) Mechanism of a transcriptional cross talk between transforming growth factor-beta-regulated Smad3 and Smad4 proteins and orphan nuclear receptor hepatocyte nuclear factor-4. Mol. Biol. Cell14 (3): 1279-94. [PMID:12631740]

10. Duncan SA, Manova K, Chen WS, Hoodless P, Weinstein DC, Bachvarova RF, Darnell JE. (1994) Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc. Natl. Acad. Sci. U.S.A.91 (16): 7598-602. [PMID:8052626]

11. Duncan SA, Nagy A, Chan W. (1997) Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos. Development124 (2): 279-87. [PMID:9053305]

12. Eeckhoute J, Moerman E, Bouckenooghe T, Lukoviak B, Pattou F, Formstecher P, Kerr-Conte J, Vandewalle B, Laine B. (2003) Hepatocyte nuclear factor 4 alpha isoforms originated from the P1 promoter are expressed in human pancreatic beta-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms. Endocrinology144 (5): 1686-94. [PMID:12697672]

13. Galson DL, Tsuchiya T, Tendler DS, Huang LE, Ren Y, Ogura T, Bunn HF. (1995) The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol. Cell. Biol.15 (4): 2135-44. [PMID:7891708]

14. Gragnoli C, Lindner T, Cockburn BN, Kaisaki PJ, Gragnoli F, Marozzi G, Bell GI. (1997) Maturity-onset diabetes of the young due to a mutation in the hepatocyte nuclear factor-4 alpha binding site in the promoter of the hepatocyte nuclear factor-1 alpha gene. Diabetes46 (10): 1648-51. [PMID:9313764]

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2A. Hepatocyte nuclear factor-4 receptors: Hepatocyte nuclear factor-4-α. Last modified on 25/03/2014. Accessed on 17/09/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=608.

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