Affiliations: Department of Diabetes and Vascular Medicine,
Peninsular Medical School,University of Exeter, Barrack Rd, Exeter EX2 5AX, UK.
Tel.: +44 798 910 7381; Fax: +44 1392 403027, E-mail:
[email protected], [email protected]
Note: [] Corresponding author
Abstract: The identification of regulatory elements in silico is an important
method for inferring function from sequence data, but it is uncertain which
methods are best. We used a novel combination of expression data from a TCF1
knockout mouse (TCF1 codes for the transcription factor HNF1α), and human
and mouse genome sequences, to search 2kb upstream of 28 genes downregulated in
TCF1 null mice compared to wild type mice. We wrote software
(http://www.BindGene.org) to search for and assign p-values to potential
binding sites. This identified 8 genes as candidates for being directly
regulated by HNF1α: LIPC, CRP, F13B, PRODH2, HSD17B2, SCL7A9, SLC16A7,
PAH. There was evidence for conservation between human and mouse for all these
regions identified as containing putative binding sites. For three of the genes
identified there was experimental evidence for an HNF1α binding site. For
comparison we also examined 25 genes up-regulated in TCF1 null mice; only one
gene was selected and there was little evidence for conservation of this
putative binding site between human and mouse. This result was consistent with
HNF1α being a gene transcription activator. Another 6
up-regulated genes had unexpectedly high p-values, suggesting that possibly
HNF1α sites have been suppressed from these genes. In
conclusion, gene expression data from transgenic animals lacking a
transcription factor can be used to identify DNA binding sites for that
factor.
