title: In silico searching of human and mouse genome data identifies known and unknown HNF1 binding sites upstream of beta-cell genes.
abstract: HNF1-alpha is a transcription factor present in beta-cells. Mutations in the HNF1-alpha gene cause maturity-onset diabetes of the young (MODY), but the exact mechanism is not known. Several studies have highlighted genes down-regulated in beta-cells lacking this gene, but it is not clear if these are directly regulated by HNF1-alpha. To better understand this, we used human and mouse genome data to examine 29 genes expressed in the beta-cell. Using an in silico approach (with software available at www.BindGene.org) we examined 2kb upstream of each gene for possible HNF1 binding sequences. In five genes we also examined 100kb upstream of each gene, but only the portions strongly conserved between humans and mice. We identified nine putative HNF1 binding sites upstream of seven genes (p<0.1 and good alignment between species or p<0.05). Six of these nine sites had some experimental corroboratory evidence and included the recently identified sites 6 and 45kb upstream of HNF4-alpha. Three novel sites were identified. These were 92bp upstream of SLC3A1, 52bp upstream of PCBD (DCOH), and 42202bp upstream of TCF2(HNF1-beta). In conclusion, our computer search identified some known HNF1 sites, and suggested three novel sites indicating these genes are very likely to be directly activated by HNF1. This should help in designing experiments to discover the mechanisms of beta-cell dysfunction due to HNF1 disruption.
authors.affiliation: Diabetes and Vascular Medicine, Peninsular Medical School, Exeter, UK.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lockwood
authors.forename: Coralie
authors.initials: C
authors.lastname: Bingham
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017931:DNA Primers; D004268:DNA-Binding Proteins; D016678:Genome; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta