Abstract
BackgroundThe arrangement of regulatory motifs in gene promoters, or promoter architecture, is the result of mutation and selection processes that have operated over many millions of years. In mammals, tissue-specific transcriptional regulation is related to the presence of specific protein-interacting DNA motifs in gene promoters. However, little is known about the relative location and spacing of these motifs. To fill this gap, we have performed a systematic search for motifs that show significant bias at specific promoter locations in a large collection of housekeeping and tissue-specific genes.ResultsWe observe that promoters driving housekeeping gene expression are enriched in particular motifs with strong positional bias, such as YY1, which are of little relevance in promoters driving tissue-specific expression. We also identify a large number of motifs that show positional bias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specific motifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis, as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictions for 559 tissue-specific motifs in mouse gene promoters.ConclusionThe study shows that motif positional bias is an important feature of mammalian proximal promoters and that it affects both general and tissue-specific motifs. Motif positional constraints define very distinct promoter architectures depending on breadth of expression and type of tissue.
Highlights
The arrangement of regulatory motifs in gene promoters, or promoter architecture, is the result of mutation and selection processes that have operated over many millions of years
The analysis identifies distinctive features of promoters driving housekeeping or tissue-specific expression, shows that a number of well-known tissue-specific regulatory motifs are subject to strong positional constraints and predicts novel regulatory elements in different tissue expression gene datasets
In this study we used four different libraries: 508 vertebrate weight matrices corresponding to known transcription factor binding sites from TRANSFAC [18]; 91 vertebrate weight matrices corresponding to known transcription factor binding sites from JASPAR, or JASPAR CORE matrices [19]; 174 weight matrices from JASPAR corresponding to putative regulatory sequences on the basis of phylogenetic conservation, or JASPAR phyloFACTS [19]; and a non-redundant set of 2080 oligomers of size 6 (6mers)
Summary
The arrangement of regulatory motifs in gene promoters, or promoter architecture, is the result of mutation and selection processes that have operated over many millions of years. It has been recently observed that a number of motifs that are likely to be important for the regulation of the expression of ribosomal protein genes are located at fixed positions within the promoter [10] It is well-known that TFBS can be arranged in particular combinations forming functional regulatory units, known as cis-regulatory modules [11,12]. Spacing between motifs can be the result of transcription factor interaction requirements in the context of particular cis-regulatory modules This type of constraints can be revealed by the analysis of relative motif positions in many different genes, with the discovery of recurrent motif location patterns or 'positional footprints'. The analysis identifies distinctive features of promoters driving housekeeping or tissue-specific expression, shows that a number of well-known tissue-specific regulatory motifs are subject to strong positional constraints and predicts novel regulatory elements in different tissue expression gene datasets
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