The development of powerful experimental strategies for functional genomics and accompanying computational tools has brought major advances in the delineation of transcriptional networks in organisms ranging from yeast to human. Regulation of transcription of eukaryotic genes is to a large extent combinatorial. Here, we used an in silico approach to identify transcription factors (TFs) that form recurring regulatory modules with c-Myc, a protein encoded by an oncogene that is frequently disregulated in human malignancies. A recent study identified, on a genomic scale, human genes whose promoters are bound by c-Myc and its heterodimer partner Max in Burkitt's lymphoma cells. Using computational methods, we identified nine TFs whose binding-site signatures are highly overrepresented in this promoter set of c-Myc targets, pointing to possible functional links between these TFs and c-Myc. Binding sites of most of these TFs are also enriched on the set of mouse homolog promoters, suggesting functional conservation. Among the enriched TFs, there are several regulators known to control cell cycle progression. Another TF in this set, EGR-1, is rapidly activated by numerous stress challenges and plays a central role in angiogenesis. Experimental investigation confirmed that c-Myc and EGR-1 bind together on several target promoters. The approach applied here is general and demonstrates how computational analysis of functional genomics experiments can identify novel modules in complex networks of transcriptional regulation.
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