We also establish a web-based tool, HNF4 Motif Finder, that can b

We also establish a web-based tool, HNF4 Motif Finder, that can be used to identify potential HNF4α-binding sites in any sequence. (HEPATOLOGY 2009.) Hepatocyte nuclear factor 4α, HNF4α (HNF4A), is a member of the nuclear receptor superfamily of ligand-dependent transcription factors (NR2A1) and a liver-enriched transcription factor (TF) that is also expressed in the kidney, pancreas, intestine, colon, and

stomach.1 Originally identified based on its ability to bind DNA response elements in the human apolipoprotein C3 (APOC3) and mouse transthyretin (Ttr) promoters,2 http://www.selleckchem.com/products/bmn-673.html HNF4α has since been shown to play a critical role in both the development of the embryo and the adult liver.3, 4 Mutations in the HNF4A coding sequence and promoter regions are linked to Maturity Onset Diabetes of the Young 1 (MODY1),5 and mutations in HNF4α response elements have been directly linked to disease, most notably in genes encoding blood coagulation factors in hemophilia and in HNF1α in MODY3.6–8 Through classical promoter analysis, functional HNF4α-binding sites have been identified in >140 genes, including those involved in the metabolism of glucose, lipids, and amino acids, as well as xenobiotics and drugs1, 4, 9 (see Supporting Table 1A for a listing of those genes). Recent genome-wide location analyses suggest

that the number of HNF4α targets may be much greater (>1000) based on widespread binding of HNF4α to promoter regions,10–12 although it is not known how many of those are functional targets. A more comprehensive selleck chemical list of direct HNF4α targets was recently made even more critical with our finding that HNF4α binds an exchangeable ligand and hence may be a potential drug target.13 HNF4α binds DNA exclusively MCE公司 as a homodimer.14, 15 The canonical HNF4α consensus sequence consists of the half site AGGTCA with one nucleotide spacer (referred to as a DR1, AGGTCAxAGGTCA).16 Whereas the number of experimentally verified HNF4α binding sequences is sizable (>217) (Supporting Tables 1A and 1B), they were derived in a biased

fashion building on the first HNF4α-binding sites,2 and subsequently on the direct repeat rules for nuclear receptor DNA binding.16 Furthermore, the total number of 13-base oligomer (13-mer) permutations is much greater than 217 (413 ∼ 67 million), and whereas HNF4α will certainly not bind all potential 13-mers, the total number of DNA sequences that will bind HNF4α is anticipated to be in the tens of thousands. Because the presence of one or more HNF4α response elements in the promoter region of a gene is a prerequisite for classification as a direct HNF4α target, it is desirable to accurately predict all the HNF4α-binding sites throughout the genome in an unbiased fashion. Recent genome-wide technologies, most notably genome-wide location analysis (i.e.

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