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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
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Mus musculus
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Homo sapiens
 Snai2
Mus musculus
 PPARA
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Mus musculus
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Mus musculus
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Transcription Factor Encyclopedia  BETA
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Isoforms

The human HNF4A gene spans ~74 kb on chromosome 20 and contains two promoters (P1 and P2) that drive the expression of many splice variants (isoforms) that differ in the variable A/B and F domains. The different promoters are used in different tissues and at different times during development.

It now appears that only 6 of the original 9 splice variants yield full length transcripts [1][2], 4 of which have been well characterized - HNF4α1 and HNF4α2 from the P1 promoter and HNF4α7 and HNF4α8 from the P2 promoter. HNF4α3 (P1-driven) and HNF4α9 (P2-driven), both of which have a different F domain, are much less well characterized but recent studies indicate that these isoforms are indeed expressed and may play a role in the development of diabetes [2][1]. New splice variants driven from the P2 promoter have also recently been identified [3].

Some functional variation between the different isoforms/splice variants have been noted both in vitro and in vivo [4][5][6]. Dysregulation of the P1 and P2-driven isoforms have also been reported in human cancers [7].

See Figure 3 under Summary.

References
  1. Huang J et al. Expression of HNF4alpha variants in pancreatic islets and Ins-1 beta cells. Diabetes Metab. Res. Rev., 24(7):533-43. (PMID 18561282)
  2. Harries LW et al. The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development. Diabetes, 57(6):1745-52. (PMID 18356407)
  3. Huang J et al. Novel P2 promoter-derived HNF4alpha isoforms with different N-terminus generated by alternate exon insertion. Exp. Cell Res., 315(7):1200-11. (PMID 19353766)
  4. Sladek FM et al. Modulation of transcriptional activation and coactivator interaction by a splicing variation in the F domain of nuclear receptor hepatocyte nuclear factor 4alpha1. Mol. Cell. Biol., 19(10):6509-22. (PMID 10490591)
  1. Torres-Padilla ME et al. Developmentally regulated N-terminal variants of the nuclear receptor hepatocyte nuclear factor 4alpha mediate multiple interactions through coactivator and corepressor-histone deacetylase complexes. J. Biol. Chem., 277(47):44677-87. (PMID 12205093)
  2. Briançon N and Weiss MC. In vivo role of the HNF4alpha AF-1 activation domain revealed by exon swapping. EMBO J., 25(6):1253-62. (PMID 16498401)
  3. Tanaka T et al. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4alpha in the pathogenesis of human cancer. J. Pathol., 208(5):662-72. (PMID 16400631)
Covalent modifications

HNF4a protein is covalently modified in a variety of ways. Most prominent among the post translational modifications is phosphorylation with more than a dozen Ser/Thr sites being modified [1] although only a handful of those sites have been definitively mapped and assigned to specific kinases: protein kinase C [2], AMPK [3], protein kinase A [4] and p38 kinase [5]. Tyrosine phosphorylation of HNF4a has also been noted but no sites have been mapped as of yet [6]. HNF4a has also been shown to be acetylayed by CBP [7] and methylated on arginines [8].

These modifications have a variety of effects on the function of the HNF4a protein, such as alteration in DNA binding, protein dimerization, transactivation and intracellular localization, and combinations thereof.

References
  1. Jiang G et al. Serine/threonine phosphorylation of orphan receptor hepatocyte nuclear factor 4. Arch. Biochem. Biophys., 340(1):1-9. (PMID 9126270)
  2. Sun K et al. Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization. Mol. Endocrinol., 21(6):1297-311. (PMID 17389749)
  3. Hong YH et al. AMP-activated protein kinase regulates HNF4alpha transcriptional activity by inhibiting dimer formation and decreasing protein stability. J. Biol. Chem., 278(30):27495-501. (PMID 12740371)
  4. Viollet B et al. Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol. Cell. Biol., 17(8):4208-19. (PMID 9234678)
  1. Guo H et al. Phosphorylation of Ser158 regulates inflammatory redox-dependent hepatocyte nuclear factor-4alpha transcriptional activity. Biochem. J., 394(Pt 2):379-87. (PMID 16351573)
  2. Ktistaki E et al. 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., 92(21):9876-80. (PMID 7568236)
  3. Soutoglou E et al. Acetylation regulates transcription factor activity at multiple levels. Mol. Cell, 5(4):745-51. (PMID 10882110)
  4. Barrero MJ and Malik S. Two functional modes of a nuclear receptor-recruited arginine methyltransferase in transcriptional activation. Mol. Cell, 24(2):233-43. (PMID 17052457)