Hepatocyte nuclear factor 4-alpha

Function

Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes. Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells.

Classification

Family (Pfam)

PF00104 Hormone_recep, PF00105 zf-C4

InterPro

HNF4-like_DBD, HNF4_LBD, NHR-like_dom_sf, Nucl_hrmn_rcpt_lig-bd, Nuclear_hormone_rcpt_NR2, Nuclear_hrmn_rcpt, Znf_hrmn_rcpt, Znf_NHR/GATA

Functional cluster

Homeobox & Zinc-Finger Transcription Factors

Experimental structures · PDB · 8

• 1PZL X-ray 2.10A
• 3CBB X-ray 2.00A
• 3FS1 X-ray 2.20A
• 4B7W X-ray 4.00A
• 4IQR X-ray 2.90A
• 6CHT X-ray 3.17A
• 8C1L X-ray 2.00A
• 9IBR X-ray 2.78A

A predicted model is available from AlphaFold.

Gene Ontology · 40

• GO:0000785 chromatin
• GO:0005737 cytoplasm
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0003682 chromatin binding
• GO:0003677 DNA binding
• GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0003700 DNA-binding transcription factor activity
• GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
• GO:0005504 fatty acid binding
• GO:0004879 nuclear receptor activity
• GO:0042803 protein homodimerization activity
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:1990837 sequence-specific double-stranded DNA binding
• GO:0005102 signaling receptor binding
• GO:0000976 transcription cis-regulatory region binding
• GO:0008270 zinc ion binding
• GO:0007596 blood coagulation
• GO:0030154 cell differentiation
• GO:0042632 cholesterol homeostasis
• GO:0006351 DNA-templated transcription
• GO:0042593 glucose homeostasis
• GO:0055088 lipid homeostasis
• GO:0030308 negative regulation of cell growth
• GO:0008285 negative regulation of cell population proliferation
• GO:0045892 negative regulation of DNA-templated transcription
• GO:0055091 phospholipid homeostasis
• GO:0045893 positive regulation of DNA-templated transcription
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0042752 regulation of circadian rhythm
• GO:0060398 regulation of growth hormone receptor signaling pathway
• GO:0050796 regulation of insulin secretion
• GO:0019216 regulation of lipid metabolic process
• GO:0090368 regulation of ornithine metabolic process
• GO:0006357 regulation of transcription by RNA polymerase II
• GO:0009749 response to glucose
• GO:0048511 rhythmic process
• GO:0070328 triglyceride homeostasis
• GO:0006805 xenobiotic metabolic process

Disease associations

• maturity-onset diabetes of the young type 1 MONDO:0007452
• type 2 diabetes mellitus MONDO:0005148
• Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young MONDO:0014458

Drugs targeting this protein · 1

• ALVERINE activator

Related proteins · sequence + function similarity

• Hepatocyte nuclear factor 4-alpha 0.99
• Hepatocyte nuclear factor 4-alpha 0.99
• Hepatocyte nuclear factor 4-alpha 0.95
• Hepatocyte nuclear factor 4-gamma 0.93
• Hepatocyte nuclear factor 4-gamma 0.93
• Hepatocyte nuclear factor 4-beta 0.92
• Protein ultraspiracle homolog 0.90
• Protein ultraspiracle homolog 0.90
• Retinoic acid receptor RXR-gamma 0.90
• Protein ultraspiracle homolog 0.90
• Retinoic acid receptor RXR-alpha 0.90
• Retinoic acid receptor RXR-gamma-A 0.89

Co-cited proteins · studied together in the literature

• Hepatocyte nuclear factor 4-gamma 1 shared papers
• Hepatocyte nuclear factor 4-alpha 2 shared papers
• 5'-AMP-activated protein kinase catalytic subunit alpha-2 1 shared papers
• 5'-AMP-activated protein kinase catalytic subunit alpha-1 1 shared papers
• Nuclear receptor subfamily 0 group B member 2 1 shared papers
• Nuclear hormone receptor family member nhr-49 1 shared papers
• Vitamin D3 receptor 1 shared papers
• Peroxisome proliferator-activated receptor gamma 1 shared papers
• Period circadian protein homolog 2 1 shared papers
• Retinoic acid receptor alpha 1 shared papers
• Cryptochrome-2 1 shared papers
• Period circadian protein homolog 1 1 shared papers

Literature · 23 cited papers

• HNF4A regulates the formation of hepatic progenitor cells from human iPSC-Derived endoderm by facilitating efficient recruitment of RNA Pol II. Genes (Basel) · 2018
• Nuclear receptor HNF4A transrepresses CLOCK:BMAL1 and modulates tissue-specific circadian networks. Proc. Natl. Acad. Sci. U.S.A. · 2018
• Nuclear hormone receptors: Ancient 9aaTAD and evolutionally gained NCoA activation pathways. J. Steroid Biochem. Mol. Biol. · 2019
• RNA helicase DDX3 maintains lipid homeostasis through upregulation of the microsomal triglyceride transfer protein by interacting with HNF4 and SHP. Sci. Rep. · 2017
• The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a beta cell phenotype. J. Med. Genet. · 2014
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J. Clin. Endocrinol. Metab. · 2012
• Multiple post-translational modifications in hepatocyte nuclear factor 4alpha. Biochem. Biophys. Res. Commun. · 2011
• Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. · 2007
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Structural basis for HNF-4alpha activation by ligand and coactivator binding. J. Biol. Chem. · 2004
• AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem. · 2003
• … and 11 more in the literature graph