Hepatocyte nuclear factor 4-alpha

NameHepatocyte nuclear factor 4-alpha
Synonyms
  • HNF-4-alpha
  • HNF4
  • NR2A1
  • Nuclear receptor subfamily 2 group A member 1
  • TCF-14
  • TCF14
  • Transcription factor 14
  • Transcription factor HNF-4
Gene NameHNF4A
OrganismHuman
Amino acid sequence
>lcl|BSEQ0007682|Hepatocyte nuclear factor 4-alpha
MRLSKTLVDMDMADYSAALDPAYTTLEFENVQVLTMGNDTSPSEGTNLNAPNSLGVSALC
AICGDRATGKHYGASSCDGCKGFFRRSVRKNHMYSCRFSRQCVVDKDKRNQCRYCRLKKC
FRAGMKKEAVQNERDRISTRRSSYEDSSLPSINALLQAEVLSRQITSPVSGINGDIRAKK
IASIADVCESMKEQLLVLVEWAKYIPAFCELPLDDQVALLRAHAGEHLLLGATKRSMVFK
DVLLLGNDYIVPRHCPELAEMSRVSIRILDELVLPFQELQIDDNEYAYLKAIIFFDPDAK
GLSDPGKIKRLRSQVQVSLEDYINDRQYDSRGRFGELLLLLPTLQSITWQMIEQIQFIKL
FGMAKIDNLLQEMLLGGSPSDAPHAHHPLHPHLMQEHMGTNVIVANTMPTHLSNGQMCEW
PRPRGQAATPETPQPSPPGGSGSEPYKLLPGAVATIVKPLSAIPQPTITKQEVI
Number of residues474
Molecular Weight52784.205
Theoretical pI7.46
GO Classification
Functions
  • transcription factor activity, sequence-specific DNA binding
  • receptor binding
  • fatty acid binding
  • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding
  • protein homodimerization activity
  • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding
  • RNA polymerase II activating transcription factor binding
  • transcription regulatory region DNA binding
  • zinc ion binding
  • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding
  • RNA polymerase II core promoter sequence-specific DNA binding
  • steroid hormone receptor activity
  • DNA binding
Processes
  • regulation of gastrulation
  • regulation of transcription from RNA polymerase II promoter
  • regulation of growth hormone receptor signaling pathway
  • endocrine pancreas development
  • signal transduction involved in regulation of gene expression
  • SMAD protein signal transduction
  • response to glucose
  • gene expression
  • transcription initiation from RNA polymerase II promoter
  • negative regulation of cell growth
  • lipid homeostasis
  • glucose homeostasis
  • sex differentiation
  • positive regulation of transcription, DNA-templated
  • negative regulation of cell proliferation
  • positive regulation of transcription from RNA polymerase II promoter
  • lipid metabolic process
  • regulation of lipid metabolic process
  • regulation of insulin secretion
  • phospholipid homeostasis
  • blood coagulation
  • xenobiotic metabolic process
  • ornithine metabolic process
  • triglyceride homeostasis
  • positive regulation of cholesterol homeostasis
Components
  • nucleus
  • nucleoplasm
  • cytoplasm
General FunctionZinc ion binding
Specific FunctionTranscriptionally controlled transcription factor. Binds to DNA sites required for the transcription of alpha 1-antitrypsin, apolipoprotein CIII, transthyretin genes and HNF1-alpha. May be essential for development of the liver, kidney and intestine.
Pfam Domain Function
Transmembrane RegionsNot Available
GenBank Protein ID1595752
UniProtKB IDP41235
UniProtKB Entry NameHNF4A_HUMAN
Cellular LocationNucleus
Gene sequence
>lcl|BSEQ0012799|Hepatocyte nuclear factor 4-alpha (HNF4A)
ATGCGACTCTCCAAAACCCTCGTCGACATGGACATGGCCGACTACAGTGCTGCACTGGAC
CCAGCCTACACCACCCTGGAATTTGAGAATGTGCAGGTGTTGACGATGGGCAATGACACG
TCCCCATCAGAAGGCACCAACCTCAACGCGCCCAACAGCCTGGGTGTCAGCGCCCTGTGT
GCCATCTGCGGGGACCGGGCCACGGGCAAACACTACGGTGCCTCGAGCTGTGACGGCTGC
AAGGGCTTCTTCCGGAGGAGCGTGCGGAAGAACCACATGTACTCCTGCAGATTTAGCCGG
CAGTGCGTGGTGGACAAAGACAAGAGGAACCAGTGCCGCTACTGCAGGCTCAAGAAATGC
TTCCGGGCTGGCATGAAGAAGGAAGCCGTCCAGAATGAGCGGGACCGGATCAGCACTCGA
AGGTCAAGCTATGAGGACAGCAGCCTGCCCTCCATCAATGCGCTCCTGCAGGCGGAGGTC
CTGTCCCGACAGATCACCTCCCCCGTCTCCGGGATCAACGGCGACATTCGGGCGAAGAAG
ATTGCCAGCATCGCAGATGTGTGTGAGTCCATGAAGGAGCAGCTGCTGGTTCTCGTTGAG
TGGGCCAAGTACATCCCAGCTTTCTGCGAGCTCCCCCTGGACGACCAGGTGGCCCTGCTC
AGAGCCCATGCTGGCGAGCACCTGCTGCTCGGAGCCACCAAGAGATCCATGGTGTTCAAG
GACGTGCTGCTCCTAGGCAATGACTACATTGTCCCTCGGCACTGCCCGGAGCTGGCGGAG
ATGAGCCGGGTGTCCATACGCATCCTTGACGAGCTGGTGCTGCCCTTCCAGGAGCTGCAG
ATCGATGACAATGAGTATGCCTACCTCAAAGCCATCATCTTCTTTGACCCAGATGCCAAG
GGGCTGAGCGATCCAGGGAAGATCAAGCGGCTGCGTTCCCAGGTGCAGGTGAGCTTGGAG
GACTACATCAACGACCGCCAGTATGACTCGCGTGGCCGCTTTGGAGAGCTGCTGCTGCTG
CTGCCCACCTTGCAGAGCATCACCTGGCAGATGATCGAGCAGATCCAGTTCATCAAGCTC
TTCGGCATGGCCAAGATTGACAACCTGTTGCAGGAGATGCTGCTGGGAGGGTCCCCCAGC
GATGCACCCCATGCCCACCACCCCCTGCACCCTCACCTGATGCAGGAACATATGGGAACC
AACGTCATCGTTGCCAACACAATGCCCACTCACCTCAGCAACGGACAGATGTGTGAGTGG
CCCCGACCCAGGGGACAGGCAGCCACCCCTGAGACCCCACAGCCCTCACCGCCAGGTGGC
TCAGGGTCTGAGCCCTATAAGCTCCTGCCGGGAGCCGTCGCCACAATCGTCAAGCCCCTC
TCTGCCATCCCCCAGCCGACCATCACCAAGCAGGAAGTTATCTAG
GenBank Gene IDX87870
GeneCard IDNot Available
GenAtlas IDNot Available
HGNC IDHGNC:5024
Chromosome Location20
Locus20q12-q13.1
References
  1. Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, Talianidis I: Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4. Gene. 1996 Sep 16;173(2):275-80. 8964514
  2. Drewes T, Senkel S, Holewa B, Ryffel GU: Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol. 1996 Mar;16(3):925-31. 8622695
  3. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI: Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458-60. 8945471
  4. Deloukas P, Matthews LH, Ashurst J, Burton J, Gilbert JG, Jones M, Stavrides G, Almeida JP, Babbage AK, Bagguley CL, Bailey J, Barlow KF, Bates KN, Beard LM, Beare DM, Beasley OP, Bird CP, Blakey SE, Bridgeman AM, Brown AJ, Buck D, Burrill W, Butler AP, Carder C, Carter NP, Chapman JC, Clamp M, Clark G, Clark LN, Clark SY, Clee CM, Clegg S, Cobley VE, Collier RE, Connor R, Corby NR, Coulson A, Coville GJ, Deadman R, Dhami P, Dunn M, Ellington AG, Frankland JA, Fraser A, French L, Garner P, Grafham DV, Griffiths C, Griffiths MN, Gwilliam R, Hall RE, Hammond S, Harley JL, Heath PD, Ho S, Holden JL, Howden PJ, Huckle E, Hunt AR, Hunt SE, Jekosch K, Johnson CM, Johnson D, Kay MP, Kimberley AM, King A, Knights A, Laird GK, Lawlor S, Lehvaslaiho MH, Leversha M, Lloyd C, Lloyd DM, Lovell JD, Marsh VL, Martin SL, McConnachie LJ, McLay K, McMurray AA, Milne S, Mistry D, Moore MJ, Mullikin JC, Nickerson T, Oliver K, Parker A, Patel R, Pearce TA, Peck AI, Phillimore BJ, Prathalingam SR, Plumb RW, Ramsay H, Rice CM, Ross MT, Scott CE, Sehra HK, Shownkeen R, Sims S, Skuce CD, Smith ML, Soderlund C, Steward CA, Sulston JE, Swann M, Sycamore N, Taylor R, Tee L, Thomas DW, Thorpe A, Tracey A, Tromans AC, Vaudin M, Wall M, Wallis JM, Whitehead SL, Whittaker P, Willey DL, Williams L, Williams SA, Wilming L, Wray PW, Hubbard T, Durbin RM, Bentley DR, Beck S, Rogers J: The DNA sequence and comparative analysis of human chromosome 20. Nature. 2001 Dec 20-27;414(6866):865-71. 11780052
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. 15489334
  6. Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B: Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene. 1994 Sep 30;147(2):269-72. 7926813
  7. Ktistaki E, Ktistakis NT, Papadogeorgaki E, Talianidis I: Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential. Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9876-80. 7568236
  8. Hong YH, Varanasi US, Yang W, Leff T: AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J Biol Chem. 2003 Jul 25;278(30):27495-501. Epub 2003 May 9. 12740371
  9. Yokoyama A, Katsura S, Ito R, Hashiba W, Sekine H, Fujiki R, Kato S: Multiple post-translational modifications in hepatocyte nuclear factor 4alpha. Biochem Biophys Res Commun. 2011 Jul 15;410(4):749-53. doi: 10.1016/j.bbrc.2011.06.033. Epub 2011 Jun 17. 21708125
  10. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. 24275569
  11. Duda K, Chi YI, Shoelson SE: Structural basis for HNF-4alpha activation by ligand and coactivator binding. J Biol Chem. 2004 May 28;279(22):23311-6. Epub 2004 Feb 24. 14982928
  12. Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI: Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY. Diabetes. 1997 Oct;46(10):1652-7. 9313765
  13. Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT: A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. Diabetologia. 1997 Jul;40(7):859-62. 9243109
  14. Moller AM, Urhammer SA, Dalgaard LT, Reneland R, Berglund L, Hansen T, Clausen JO, Lithell H, Pedersen O: Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM. Diabetologia. 1997 Aug;40(8):980-3. 9267996
  15. Hani EH, Suaud L, Boutin P, Chevre JC, Durand E, Philippi A, Demenais F, Vionnet N, Furuta H, Velho G, Bell GI, Laine B, Froguel P: A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus. J Clin Invest. 1998 Feb 1;101(3):521-6. 9449683
  16. Navas MA, Munoz-Elias EJ, Kim J, Shih D, Stoffel M: Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). Diabetes. 1999 Jul;48(7):1459-65. 10389854
  17. Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT: Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007 Apr;4(4):e118. 17407387
  18. Stanescu DE, Hughes N, Kaplan B, Stanley CA, De Leon DD: Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012 Oct;97(10):E2026-30. doi: 10.1210/jc.2012-1356. Epub 2012 Jul 16. 22802087
  19. Hamilton AJ, Bingham C, McDonald TJ, Cook PR, Caswell RC, Weedon MN, Oram RA, Shields BM, Shepherd M, Inward CD, Hamilton-Shield JP, Kohlhase J, Ellard S, Hattersley AT: The HNF4A R76W mutation causes atypical dominant Fanconi syndrome in addition to a beta cell phenotype. J Med Genet. 2014 Mar;51(3):165-9. doi: 10.1136/jmedgenet-2013-102066. Epub 2013 Nov 27. 24285859