HNF4A hepatocyte nuclear factor 4 alpha [Homo sapiens (human)] - Gene

Summary

Official Symbol: HNF4Aprovided by HGNC
Official Full Name: hepatocyte nuclear factor 4 alphaprovided by HGNC
Primary source: HGNC:HGNC:5024
See related: Ensembl:ENSG00000101076 MIM:600281; AllianceGenome:HGNC:5024
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: TCF; HNF4; MODY; FRTS4; MODY1; NR2A1; TCF14; HNF4a7; HNF4a8; HNF4a9; NR2A21; TCF-14; HNF4alpha
Summary: The protein encoded by this gene is a nuclear transcription factor which binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene may play a role in development of the liver, kidney, and intestines. Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I. Alternative splicing of this gene results in multiple transcript variants encoding several different isoforms. [provided by RefSeq, Apr 2012]
Expression: Biased expression in duodenum (RPKM 37.7), colon (RPKM 32.8) and 7 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 20q13.12

Exon count:: 15

Annotation release	Status	Assembly	Chr	Location
RS_2023_10	current	GRCh38.p14 (GCF_000001405.40)	20	NC_000020.11 (44355699..44434596)
RS_2023_10	current	T2T-CHM13v2.0 (GCF_009914755.1)	20	NC_060944.1 (46090439..46170188)
105.20220307	previous assembly	GRCh37.p13 (GCF_000001405.25)	20	NC_000020.10 (42984339..43063236)

Chromosome 20 - NC_000020.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Association between HNF4A rs1800961 polymorphisms and gallstones in a Taiwanese population.
Title: Association between HNF4A rs1800961 polymorphisms and gallstones in a Taiwanese population.
Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids.
Title: Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids.
Insulin Determines Transforming Growth Factor beta Effects on Hepatocyte Nuclear Factor 4alpha Transcription in Hepatocytes.
Title: Insulin Determines Transforming Growth Factor β Effects on Hepatocyte Nuclear Factor 4α Transcription in Hepatocytes.
Ectopic expression of HNF4alpha in Het1A cells induces an invasive phenotype.
Title: Ectopic expression of HNF4α in Het1A cells induces an invasive phenotype.
The HNF4A-CHPF pathway promotes proliferation and invasion through interactions with MAD1L1 in glioma.
Title: The HNF4A-CHPF pathway promotes proliferation and invasion through interactions with MAD1L1 in glioma.
HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer.
Title: HNF4A-BAP31-VDAC1 axis synchronously regulates cell proliferation and ferroptosis in gastric cancer.
TUBB2B facilitates progression of hepatocellular carcinoma by regulating cholesterol metabolism through targeting HNF4A/CYP27A1.
Title: TUBB2B facilitates progression of hepatocellular carcinoma by regulating cholesterol metabolism through targeting HNF4A/CYP27A1.
Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4alpha and Promotes Extrahepatic Carcinogenesis.
Title: Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis.
High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy.
Title: High-Throughput Sequencing Data Reveal an Antiangiogenic Role of HNF4A-Mediated CACNA1A/VEGFA Axis in Proliferative Diabetic Retinopathy.
HNF4alpha, SP1 and c-myc are master regulators of CNS autoimmunity.
Title: HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity.

Submit: New GeneRIF Correction See all GeneRIFs (447)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Familial hyperinsulinism MedGen: C3888018 GeneReviews: Familial Hyperinsulinism	Compare labs
Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young MedGen: C4014962 OMIM: 616026 GeneReviews: Not available	Compare labs
Maturity-onset diabetes of the young type 1 MedGen: C1852093 OMIM: 125850 GeneReviews: Maturity-Onset Diabetes of the Young Overview	Compare labs
Type 2 diabetes mellitus MedGen: C0011860 OMIM: 125853 GeneReviews: WFS1 Spectrum Disorder	Compare labs

EBI GWAS Catalog

Description
Biological, clinical and population relevance of 95 loci for blood lipids. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common variants at 30 loci contribute to polygenic dyslipidemia. EBI GWAS Catalog EBI GWAS CatalogPubMed
Discovery and refinement of loci associated with lipid levels. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association and population genetic analysis of C-reactive protein in African American and Hispanic American women. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. EBI GWAS Catalog EBI GWAS CatalogPubMed
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis of genome-wide association studies in &gt;80 000 subjects identifies multiple loci for C-reactive protein levels. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

PMC151122P1 (e-PCR)
- UniSTS:271135

PMC99906P2 (e-PCR)
- UniSTS:273697

SHGC-33922 (e-PCR)
- UniSTS:72283

RH69732 (e-PCR)
- UniSTS:37987

NoName (e-PCR)
- UniSTS:484196

Hnf4a (e-PCR), detects polymorphism
- UniSTS:464792

RH76001 (e-PCR)
- UniSTS:87196

GDB:451872 (e-PCR)
- UniSTS:157386

D20S1127 (e-PCR)
- UniSTS:63691

RH66101 (e-PCR)
- UniSTS:59098

RH66546 (e-PCR)
- UniSTS:223

Hnf4 (e-PCR), detects polymorphism
- UniSTS:143357

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription activator activity, RNA polymerase II-specific	ISS Inferred from Sequence or Structural Similarity more info
enables DNA-binding transcription factor activity	IDA Inferred from Direct Assay more info	PubMed
enables DNA-binding transcription factor activity, RNA polymerase II-specific	ISA Inferred from Sequence Alignment more info
enables RNA polymerase II cis-regulatory region sequence-specific DNA binding	IBA Inferred from Biological aspect of Ancestor more info
enables RNA polymerase II-specific DNA-binding transcription factor binding	ISS Inferred from Sequence or Structural Similarity more info
enables chromatin binding	IEA Inferred from Electronic Annotation more info
enables fatty acid binding	IDA Inferred from Direct Assay more info	PubMed
enables nuclear receptor activity	IBA Inferred from Biological aspect of Ancestor more info
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables protein homodimerization activity	IDA Inferred from Direct Assay more info	PubMed
enables sequence-specific double-stranded DNA binding	IDA Inferred from Direct Assay more info	PubMed
enables signaling receptor binding	IDA Inferred from Direct Assay more info	PubMed
enables transcription cis-regulatory region binding	IDA Inferred from Direct Assay more info	PubMed
enables zinc ion binding	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
involved_in anatomical structure development	IBA Inferred from Biological aspect of Ancestor more info
involved_in blood coagulation	IDA Inferred from Direct Assay more info	PubMed
involved_in cell differentiation	IBA Inferred from Biological aspect of Ancestor more info
involved_in cholesterol homeostasis	ISS Inferred from Sequence or Structural Similarity more info
involved_in glucose homeostasis	ISS Inferred from Sequence or Structural Similarity more info
involved_in intracellular receptor signaling pathway	IEA Inferred from Electronic Annotation more info
involved_in lipid homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in lipid metabolic process	IEA Inferred from Electronic Annotation more info
involved_in negative regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in negative regulation of cell growth	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in negative regulation of cell population proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in ornithine metabolic process	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in phospholipid homeostasis	ISS Inferred from Sequence or Structural Similarity more info
involved_in positive regulation of DNA-templated transcription	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info
acts_upstream_of_or_within positive regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in positive regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of circadian rhythm	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in regulation of gastrulation	IEA Inferred from Electronic Annotation more info
involved_in regulation of insulin secretion	ISS Inferred from Sequence or Structural Similarity more info
involved_in regulation of lipid metabolic process	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of transcription by RNA polymerase II	IDA Inferred from Direct Assay more info	PubMed
involved_in regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
involved_in response to glucose	ISS Inferred from Sequence or Structural Similarity more info
involved_in rhythmic process	IEA Inferred from Electronic Annotation more info
involved_in sex differentiation	IEA Inferred from Electronic Annotation more info
involved_in signal transduction involved in regulation of gene expression	IEA Inferred from Electronic Annotation more info
involved_in transcription by RNA polymerase II	IEA Inferred from Electronic Annotation more info
involved_in triglyceride homeostasis	ISS Inferred from Sequence or Structural Similarity more info
involved_in xenobiotic metabolic process	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
part_of chromatin	ISA Inferred from Sequence Alignment more info
located_in cytoplasm	IDA Inferred from Direct Assay more info	PubMed
located_in nucleoplasm	IDA Inferred from Direct Assay more info
located_in nucleoplasm	TAS Traceable Author Statement more info
located_in nucleus	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: hepatocyte nuclear factor 4-alpha

Names: HNF4A wild type; HNF4alpha10/11/12; hepatic nuclear factor 4 alpha; nuclear receptor subfamily 2 group A member 1; transcription factor 14; transcription factor HNF-4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_009818.1 RefSeqGene

Range

5001..82045

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_483

mRNA and Protein(s)

NM_000457.6 → NP_000448.3 hepatocyte nuclear factor 4-alpha isoform 2

See identical proteins and their annotated locations for NP_000448.3

Status: REVIEWED

Description

Transcript Variant: This variant (2) encodes the longest isoform (2, also known as HNF4alpha2).

Source sequence(s)

AL132772

Consensus CDS

CCDS13330.1

UniProtKB/Swiss-Prot

A5JW41, B2RPP8, O00659, O00723, P41235, Q14540, Q5QPB8, Q6B4V5, Q6B4V6, Q6B4V7, Q92653, Q92654, Q92655, Q99864, Q9NQH0

UniProtKB/TrEMBL

B6ZGT3, F1D8T1

Related

ENSP00000312987.3, ENST00000316099.10

Conserved Domains (2) summary

cd06931
Location:151 → 373

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:60 → 135

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001030003.3 → NP_001025174.1 hepatocyte nuclear factor 4-alpha isoform 4

See identical proteins and their annotated locations for NP_001025174.1

Status: REVIEWED

Description

Transcript Variant: This variant (4) contains an alternate 5' terminal exon (resulting in translation initiation from an alternate upstream start codon) and uses an alternate in-frame donor splice site in the 3' coding region compared to variant 2. The resulting shorter isoform (4, also known as HNF4alpha7) has a distinct N-terminus and lacks a 10 aa protein segment in the C-terminal region compared to isoform 2.

Source sequence(s)

AL117382, AL132772, AW134564, AY680696

Consensus CDS

CCDS46604.1

UniProtKB/TrEMBL

B6ZGT3

Related

ENSP00000396216.1, ENST00000457232.5

Conserved Domains (2) summary

cd06931
Location:129 → 351

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:38 → 113

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001030004.3 → NP_001025175.1 hepatocyte nuclear factor 4-alpha isoform 6

See identical proteins and their annotated locations for NP_001025175.1

Status: REVIEWED

Description

Transcript Variant: This variant (6) contains an alternate 5' terminal exon (resulting in translation initiation from an alternate upstream start codon) and differs at the 3' end that causes a frame-shift compared to variant 2. The resulting shorter isoform (6, also known as HNF4alpha9) has distinct N- and C-termini compared to isoform 2.

Source sequence(s)

AL117382, AL132772, AY680698

Consensus CDS

CCDS68131.1

UniProtKB/TrEMBL

A0A087WXV4

Related

ENSP00000476609.1, ENST00000609795.5

Conserved Domains (2) summary

cd06931
Location:129 → 351

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:38 → 113

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001258355.2 → NP_001245284.1 hepatocyte nuclear factor 4-alpha isoform 7

See identical proteins and their annotated locations for NP_001245284.1

Status: REVIEWED

Description

Transcript Variant: This variant (7) contains an additional coding exon in the 5' region that results in translation initiation from an alternate downstream start codon compared to variant 2. The resulting shorter isoform (7) has a distinct N-terminus compared to isoform 2.

Source sequence(s)

AL132772, AW134564, BP274413, HQ692869, Z49825

UniProtKB/TrEMBL

B6ZGT3

Conserved Domains (2) summary

cd06931
Location:144 → 366

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:53 → 128

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001287182.2 → NP_001274111.1 hepatocyte nuclear factor 4-alpha isoform 8

Status: REVIEWED

Description

Transcript Variant: This variant (8) differs at the 5' end (resulting in translation initiation from an alternate upstream start codon) and uses an alternate in-frame donor splice site in the 3' coding region compared to variant 2. The resulting shorter isoform (8, also known as HNF4alpha10) has a distinct N-terminus and lacks a 10 aa protein segment in the C-terminal region compared to isoform 2.

Source sequence(s)

AL117382, AL132772, AW134564, AY680696, FJ608822

UniProtKB/TrEMBL

B6ZGT3

Conserved Domains (2) summary

cd06931
Location:126 → 348

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:35 → 110

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001287183.2 → NP_001274112.1 hepatocyte nuclear factor 4-alpha isoform 9

Status: REVIEWED

Description

Transcript Variant: This variant (9) differs at the 5' end, which results in translation initiation from an alternate upstream start codon compared to variant 2. The resulting shorter isoform (9, also known as HNF4alpha11) has a distinct N-terminus compared to isoform 2.

Source sequence(s)

AL117382, AL132772

UniProtKB/TrEMBL

B6ZGT3

Conserved Domains (2) summary

cd06931
Location:126 → 348

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:35 → 110

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_001287184.2 → NP_001274113.1 hepatocyte nuclear factor 4-alpha isoform 10

Status: REVIEWED

Description

Transcript Variant: This variant (10) differs at the 5' end (resulting in translation initiation from an alternate upstream start codon) and at the 3' end (that causes a frame-shift) compared to variant 2. The resulting shorter isoform (10, also known as HNF4alpha12) has distinct N- and C-termini compared to isoform 2.

Source sequence(s)

AL117382, AL132772, AY680698, BC137539, FJ608822

UniProtKB/TrEMBL

A0A087WXV4

Conserved Domains (2) summary

cd06931
Location:126 → 348

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:35 → 110

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_175914.5 → NP_787110.2 hepatocyte nuclear factor 4-alpha isoform 5

See identical proteins and their annotated locations for NP_787110.2

Status: REVIEWED

Description

Transcript Variant: This variant (5) contains an alternate 5' terminal exon, which results in translation initiation from an alternate upstream start codon compared to variant 2. The resulting shorter isoform (5, also known as HNF4alpha8) has a distinct N-terminus compared to isoform 2.

Source sequence(s)

AL117382, AL132772

Consensus CDS

CCDS42876.1

UniProtKB/TrEMBL

B6ZGT3, F1D8T0

Related

ENSP00000315180.4, ENST00000316673.9

Conserved Domains (2) summary

cd06931
Location:129 → 351

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:38 → 113

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_178849.3 → NP_849180.1 hepatocyte nuclear factor 4-alpha isoform 1

See identical proteins and their annotated locations for NP_849180.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) uses an alternate in-frame donor splice site in the 3' coding region compared to variant 2. The resulting shorter isoform (1, also known as HNF4alpha1) lacks a 10 aa protein segment compared to isoform 2.

Source sequence(s)

AL132772, AW134564, BP274413, HQ692860

Consensus CDS

CCDS46605.1

UniProtKB/TrEMBL

B6ZGT3, F1D8S2

Related

ENSP00000412111.1, ENST00000415691.2

Conserved Domains (2) summary

cd06931
Location:151 → 373

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:60 → 135

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers
NM_178850.3 → NP_849181.1 hepatocyte nuclear factor 4-alpha isoform 3

See identical proteins and their annotated locations for NP_849181.1

Status: REVIEWED

Description

Transcript Variant: This variant (3) has a different 3' end that causes a frame-shift compared to variant 2. The resulting shorter isoform (3, also known as HNF4alpha3) has a distinct C-terminus compared to isoform 2.

Source sequence(s)

AL132772, BC137539, BP274413

Consensus CDS

CCDS13331.1

UniProtKB/TrEMBL

A0A087WXV4

Related

ENSP00000410911.2, ENST00000443598.6

Conserved Domains (2) summary

cd06931
Location:151 → 373

NR_LBD_HNF4_like; The ligand binding domain of heptocyte nuclear factor 4, which is explosively expanded in nematodes

cd06960
Location:60 → 135

NR_DBD_HNF4A; DNA-binding domain of heptocyte nuclear factor 4 (HNF4) is composed of two C4-type zinc fingers