Disease relevance of HNF4A

• To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals [1].
• In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310) [2].
• This finding shows that the majority of MODY mutations in a central European population are local and that other MODY genes could be responsible for autosomal dominant transmission of diabetes mellitus [3].
• In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes [4].
• AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY [5].

Psychiatry related information on HNF4A

• In revealing distinct mechanisms through which HLH motifs modulate the activity of TCFs, our results therefore provide further insight into the role of HLH motifs in regulating TCF function and how the inhibitory properties of the trans-acting Id HLH proteins are themselves regulated by phosphorylation [6].
• A critique of Mody, Studdert-Kennedy, and Brady's "Speech perception deficits in poor readers: auditory processing or phonological coding?" [7].

High impact information on HNF4A

• The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC) [8].
• We show here that beta-catenin and TCF inversely control the expression of the EphB2/EphB3 receptors and their ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis [9].
• Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB [9].
• In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei [10].
• Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes [10].

Chemical compound and disease context of HNF4A

• Whereas subjects with positive GADA or Type II diabetes have impaired insulin sensitivity with increasing glucose concentrations, MODY mutation carriers seem to be protected from the effect of glucose toxicity [4].
• In hepatoma cells that expressed GR and HNF-4, reporter-activity was inhibited by Dex [11].
• This study adds further support for the notion that the recovery from hemophilia at puberty may not only be related to an intact androgen-responsive element but also to the degree of disruption of the HNF-4-binding site [12].
• Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4alpha/MODY1 gene [13].
• C2 was specific to hepatoma cells and contained hepatocyte nuclear factor-4 (HNF-4) [14].

Biological context of HNF4A

• This is the first case of MODY due to a balanced translocation, and it provides evidence to confirm the crucial role of an upstream regulator of HNF4A gene expression in the beta-cell [15].
• We genotyped haplotype-tagging SNPs (htSNPs) across the two promoter regions and the coding region of HNF4A in individuals with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) from the Amish Family Diabetes Study (AFDS) to test for association with type 2 diabetes [16].
• Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population [2].
• Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes [17].
• Hepatocyte nuclear factor 4-alpha (HNF4A) is a transcription factor located on chromosome 20q13 that regulates expression of genes involved in glucose metabolism and homeostasis [16].

Anatomical context of HNF4A

• PUFA repress the promoter activity only in HNF4 alpha-cotransfected HeLa cells, whereas they have no effects on the promoter activity in HNF1 alpha-cotransfected HeLa cells [18].
• Maturity onset diabetes of the young, subtype 1 (MODY1), is associated with defective glucose-dependent insulin secretion from pancreatic beta cells [19].
• It has recently been reported that HNF4 alpha transcription is driven almost exclusively by the P2 promoter in pancreatic islets [20].
• 4. Important factors for apoCII gene transcription appear to be HNF-4 and RXR-alpha/T3R-beta which binds to a thyroid response element of the proximal promoter [21].
• EMSA showed that HNF-4alpha from nuclear extracts of differentiated intestinal epithelial cells (Caco-2) bound with high affinity to the predicted HNF-4 binding site [22].

Associations of HNF4A with chemical compounds

• Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations [23].
• Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression [24].
• We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically [25].
• Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding [26].
• The binding of HNF4 alpha to its cognate sites is specifically inhibited by polyunsaturated fatty acyl coenzyme A in vitro [18].

Physical interactions of HNF4A

• The TGF-beta pathway activates SMAD3/4 proteins which interact with HNF-4 bound to the apoCIII promoter and enhancer and increase its activity [21].
• Three TCF/LEF-binding sites within human CER1 promoter were conserved in chimpanzee CER1 promoter, two in cow and dog Cer1 promoters, but not in rodent Cer1 promoters [27].
• These data strongly suggest that the mechanism by which PUFA suppress the glucose-6-phosphatase gene transcription involves an inhibition of the binding of HNF4 alpha to its cognate sites in the presence of polyunsaturated fatty acyl-CoA thioesters [18].
• FKHR interacted with the DNA binding domain of HNF-4 and inhibited HNF-4 binding to the cognate DNA [28].
• Complex interactions between SP1 bound to multiple distal regulatory sites and HNF-4 bound to the proximal promoter lead to transcriptional activation of liver-specific human APOCIII gene [29].

Enzymatic interactions of HNF4A

• Furthermore, the binding affinity of HNF-4 with phosphorylated FKHR significantly decreased in comparison to that with unphosphorylated FKHR [28].

Regulatory relationships of HNF4A

• This suggests that HNF-4 regulates MTP gene expression either directly or indirectly through elevated HNF-1 levels [30].
• In HeLa cells, the glucose-6-phosphatase promoter activity is induced by the co-expression of HNF4 alpha or HNF1 alpha [18].
• Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes [31].
• Characterization of the human HNF1 alpha gene promoter identified a consensus bile acid response element that binds and is activated by HNF4 alpha [32].
• Moreover, we found that WT1 down-regulates hepatocyte nuclear factor 4 (HNF-4), a factor that is essential to maintain liver function and metabolic regulation in the mature organ [33].

Co-localisations of HNF4A

• We also show that HNF4alpha, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4alpha and GATA4 is critical for the synergistic response [34].

Other interactions of HNF4A

• In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree [35].
• IL-1beta inhibited human CYP7A1 reporter activity via the HNF4 alpha binding site [36].
• These results indicate that two nuclear receptors, HNF-4 and FXR, are closely involved in MTP gene expression, and the results provide evidence for a novel interaction between bile acids and lipoprotein metabolism [30].
• OBJECTIVE: Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 alpha, HNF-1 beta, and HNF-4 alpha are associated with maturity-onset diabetes of the young (MODY) and are believed to cause this form of diabetes by impairing pancreatic beta-cell function [37].
• Recently, we found that transcriptional factors, hepatocyte nuclear factor (HNF)-1 alpha, HNF-4 alpha and HNF-4 gamma were essential for the expression of DD4 mRNA, which is a major form of DDs [38].

Analytical, diagnostic and therapeutic context of HNF4A

• The promotor and coding regions including intron-exon boundaries of HNF4A, GCK, and TCF1 were examined by denaturing HPLC and/or direct sequencing [39].
• The ability of HNF4 alpha to bind this sequence was confirmed using gel shift analysis [19].
• Chromatin immunoprecipitation assays provide evidence that endogenous HNF-4 and HNF-1 can bind these elements in chromatin [30].
• The in vitro pull-down and in vivo co-immunoprecipitation experiments showed the direct interaction between SREBP-2 and HNF-4 [40].
• In the future, the availability of gene chip technology may allow rapid screening of mitochondrial and MODY mutations [41].

References