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Extensive low-affinity transcriptional interactions in the yeast genome

Center for Studies in Physics and Biology, Rockefeller University, New York, New York 10021, USA

Major experimental and computational efforts are targeted at the characterization of transcriptional networks on a genomic scale. The ultimate goal of many of these studies is to construct networks associating transcription factors with genes via well-defined binding sites. Weaker regulatory interactions other than those occurring at high-affinity binding sites are largely ignored and are not well understood. Here I show that low-affinity interactions are abundant in vivo and quantifiable from current high-throughput ChIP experiments. I develop algorithms that predict DNA-binding energies from sequences and ChIP data across a wide dynamic range of affinities and use them to reveal widespread functionality of low-affinity transcription factor binding. Evolutionary analysis suggests that binding energies of many transcription factors are conserved even in promoters lacking classical binding sites. Gene expression analysis shows that such promoters can generate significant expression. I estimate that while only a small percentage of the genome is strongly regulated by a typical transcription factor, up to an order of magnitude more may be involved in weaker interactions. Low-affinity transcription factor–DNA interaction may therefore be important both evolutionarily and functionally.

Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.5113606

[Supplemental material is available online at www.genome.org and at http://uqbar.rockefeller.edu/~atanay/prego.]

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