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API HNF4G  hepatocyte nuclear factor 4, gamma |
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View recent activityHepatocyte nuclear factor 4 gamma (HNF4G) is a member of the HNF4 (NR2A) transcription factors[1] that include in humans the HNF4A and HNF4G genes as well as an inactive HNF4G-related pseudogene[2]. In Xenopus and chicken HNF1B is found as a distinct member that has been lost during mammalian evolution (further data on the phylogeny of the HNF4 genes[1]). The various domains of HNF4G, HNF4A and HNF4B are most similar (see Fig. 1) implying functional redundancy.
The genomic structure of human HNF4G reveals 12 exons with two alternatives promoters that are used in a tissue-specific manner and encode two proteins with distinct N-termini[3]. The far upstream promoter generates by alternative splicing a transcript lacking the N-terminus encoded by the transcript derived from the downstream promoter (Fig. 2).
HNF4G was identified by screening a kidney cDNA library with a Xenopus probe for HNF4B[4]. The expression pattern of HNF4G is distinct from HNF4A with predominant expression in the pancreas, kidney, small intestine and testis[4]. A similar expression pattern has also been reported in the mouse and by immunohistochemistry protein expression was observed in the glomeruli of the kidney, in all endocrine cells of the islets of Langerhans, in colonic cells (predominantly in the lower part of the crypts) as well as in spermatocytes and spermatozoa[5]. In a comparative anaylsis of 49 nuclear receptors HNF4G is assigned to the category with wide expression and high expression in gastroenteric tissues[6].
The function of HNF4G is quite elusive, as mutation screening did not reveal any changes associated with type 2 diabetes[3][7]. In addition, HNF4G knockout mice have only minor differences compared with littermates: They had a lower energy expenditure and a reduced activity during night time that resulted in in a higher body weight despite having reduced intake of food and water. In addition these mice were less inclined to build nest and were found to spend more time in a passive state during the forced swim test[8]. In transgenic mice with knockdown of HNF4G by RNA interference no effect was apparent[9]. Possibly, HNF4A takes over some function of HNF4G in these manipulated mice.
- Bertrand S et al. Evolutionary genomics of nuclear receptors: from twenty-five ancestral genes to derived endocrine systems. Mol. Biol. Evol., 21(10):1923-37. (PMID 15229292)
- Maglich JM et al. Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes. Genome Biol., 2(8):RESEARCH0029. (PMID 11532213)
- Plengvidhya N et al. Hepatocyte nuclear factor-4gamma: cDNA sequence, gene organization, and mutation screening in early-onset autosomal-dominant type 2 diabetes. Diabetes, 48(10):2099-102. (PMID 10512380)
- Drewes T et al. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol. Cell. Biol., 16(3):925-31. (PMID 8622695)
- Taraviras S et al. Primary structure, chromosomal mapping, expression and transcriptional activity of murine hepatocyte nuclear factor 4gamma. Biochim. Biophys. Acta, 1490(1-2):21-32. (PMID 10786614)
- Bookout AL et al. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell, 126(4):789-99. (PMID 16923397)
- Hara M et al. No diabetes-associated mutations in the coding region of the hepatocyte nuclear factor-4gamma gene (HNF4G) in Japanese patients with MODY. Diabetologia, 43(8):1064-9. (PMID 10990086)
- Gerdin AK et al. Phenotypic screening of hepatocyte nuclear factor (HNF) 4-gamma receptor knockout mice. Biochem. Biophys. Res. Commun., 349(2):825-32. (PMID 16945327)
- Kirilov M et al. Germ line transmission and expression of an RNAi cassette in mice generated by a lentiviral vector system. Transgenic Res., 16(6):783-93. (PMID 17682835)
   |  FIGURE 1 Comparison of activation, DNA binding and ligand binding domains Alignment of the amino acid sequence of the short isoform of human HNF4G (see Fig. 2) with the human HNF4A isoform 1 (see http://www.cisreg.ca/cgo-bin/tfe/articles.pl?tfid=140) and the Xenopus HNF4B [1]. In the HNF4A and HNF4B sequences only amino acids that differ to HNF4G are shown.
A: The activation domain AF1 (see Fig. 3) of all three HNF4 proteins contains the aromatic Tyr and Phe as well as bulky Leu residues (green boxes) known to be essential for the activity of this acidic activator [2]. Note that the HNF4A protein possibly contains an additional 9 amino acids at the N-terminus [3]. B: The DNA binding domains contain two C4 zinc fingers, a P box and a T box that are highly conserved. The beta-sheets (green) and alpha helixes (yellow) are taken from the crystal structure of the HNF4A DNA complex and the hydrophobic core residues are marked with green squares [4]. The P box represents a six amino acid sequence characteristic for the HNF4 proteins. The numbering of the amino acids refers to the short isoform of HNF4G. C: Based on crystal structure analysis the ligand binding domain of HNF4G contains 10 alpha helixes (yellow) and 2 beta sheets (green) [5]. Alignment with HNF4A and HNF4B shows the high conservation that includes amino acid positions involved in dimer formation (red arrow heads) and fatty acid binding (blue arrow heads). The numbering of the amino acids refers to the short isoform of HNF4G. References
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work. |
