Nucleic Acids Research Advance Access published online on March 26, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn137
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Computational Biology |
The biological function of some human transcription factor binding motifs varies with position relative to the transcription start site
1Computational Biology Branch, National Center for Biotechnology Information and 2National Library of Medicine, National Institutes of Health, 8600 Rockville Pike, MSC 6075 Bethesda, MD 20894-6075, USA
*To whom correspondence should be addressed. Tel: +301 402 3708; Fax: +301 480 2288; Email: marino{at}ncbi.nlm.nih.gov
Received February 14, 2008. Revised March 11, 2008. Accepted March 12, 2008.
A number of previous studies have predicted transcription factor binding sites (TFBSs) by exploiting the position of genomic landmarks like the transcriptional start site (TSS). The studies’ methods are generally too computationally intensive for genome-scale investigation, so the full potential of ‘positional regulomics’ to discover TFBSs and determine their function remains unknown. Because databases often annotate the genomic landmarks in DNA sequences, the methodical exploitation of positional regulomics has become increasingly urgent. Accordingly, we examined a set of 7914 human putative promoter regions (PPRs) with a known TSS. Our methods identified 1226 eight-letter DNA words with significant positional preferences with respect to the TSS, of which only 608 of the 1226 words matched known TFBSs. Many groups of genes whose PPRs contained a common word displayed similar expression profiles and related biological functions, however. Most interestingly, our results included 78 words, each of which clustered significantly in two or three different positions relative to the TSS. Often, the gene groups corresponding to different positional clusters of the same word corresponded to diverse functions, e.g. activation or repression in different tissues. Thus, different clusters of the same word likely reflect the phenomenon of ‘positional regulation’, i.e. a word's regulatory function can vary with its position relative to a genomic landmark, a conclusion inaccessible to methods based purely on sequence. Further integrative analysis of words co-occurring in PPRs also yielded 24 different groups of genes, likely identifying cis-regulatory modules de novo. Whereas comparative genomics requires precise sequence alignments, positional regulomics exploits genomic landmarks to provide a ‘poor man's alignment’. By exploiting the phenomenon of positional regulation, it uses position to differentiate the biological functions of subsets of TFBSs sharing a common sequence motif.