The design of transcription-factor binding sites is affected by combinatorial regulation

Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
Genome biology (Impact Factor: 10.81). 02/2005; 6(12):R103. DOI: 10.1186/gb-2005-6-12-r103
Source: PubMed


Transcription factors regulate gene expression by binding to specific cis-regulatory elements in gene promoters. Although DNA sequences that serve as transcription-factor binding sites have been characterized and associated with the regulation of numerous genes, the principles that govern the design and evolution of such sites are poorly understood.
Using the comprehensive mapping of binding-site locations available in Saccharomyces cerevisiae, we examined possible factors that may have an impact on binding-site design. We found that binding sites tend to be shorter and fuzzier when they appear in promoter regions that bind multiple transcription factors. We further found that essential genes bind relatively fewer transcription factors, as do divergent promoters. We provide evidence that novel binding sites tend to appear in specific promoters that are already associated with multiple sites.
Two principal models may account for the observed correlations. First, it may be that the interaction between multiple factors compensates for the decreased specificity of each specific binding sequence. In such a scenario, binding-site fuzziness is a consequence of the presence of multiple binding sites. Second, binding sites may tend to appear in promoter regions that are subject to low selective pressure, which also allows for fuzzier motifs. The latter possibility may account for the relatively low number of binding sites found in promoters of essential genes and in divergent promoters.

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    • "Our genome holds the genetic code that potentiates its interaction with DNA binding proteins, including transcription factors such as the estrogen receptor alpha (ESR1) (Kumar et al., 1987; Kumar and Chambon, 1988; ENCODE Project Consortium et al., 2012; Wang et al., 2012). The vast majority of DNA motifs recognized by transcription factors are short sequences (ranging in size between 5 and 19 nucleotides long) that are commonly found across the genome (Wingender, 1988; Sandelin et al., 2004; Bilu and Barkai, 2005; Neph et al., 2012). However, the DNA in eukaryotic cells is progressively folded into a higher complexity structure called chromatin, where nucleosomes form the basic unit. "
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    • "Some TFs cooperatively bind to several binding sites within proximity. This can result in increased TF-DNA binding affinity and specificity (Bilu and Barkai, 2005; Hochschild and Ptashne, 1986), minimized nonfunctional binding (Wunderlich and Mirny, 2009), and decreased nucleosome occupancy (Miller and Widom, 2003; Wasson and Hartemink, 2009) and may fine-tune the expression level of target genes (Lam et al., 2008). It remains to be seen how different classes of TFBSs are organized in the context of binding sequence preference. "
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    • "We satisfied this constraint by compensating changes in ω via the target site binding energy, which is " programmable " through the binding site sequence [10]. Such a compensation has been observed in an analysis of combinatorial promoters, i.e. binding sites tend to deviate from the consensus motif when multiple TFs bind next to each other in the cis-regulatory region [35]. It is also biologically plausible as it does not interfere with the regulation of genes that are only regulated by one of the TFs or combinatorially with other TFs. "
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