Revealing the regulatory vocabulary of genomes

A powerful alternative for regulatory-element discovery is to detect local conservation within DNA sequence alignments of closely related species. However, non-optimality of sequence alignments and increasing evidence that regulatory elements ‘move around’ motivated us to develop an entirely novel solution to the problem (Pritsker et al. Genome Research 2004, 14: 99). Our non-alignment based approach extends the single-locus conservation paradigm to the entire genome, providing us with statistical power from thousands of loci simultaneously and allowing us to detect functional DNA and RNA elements with unprecedented sensitivity using only a pair of genomes (Elemento and Tavazoie Genome Biology 2005, 6(2):R18; Chan et al. PLoS Comput. Biol. 2005, 1(7): 369; Elemento and Tavazoie Methods Mol. Biol. 2007, 395:349). We have thus been able to generate comprehensive catalogues of regulatory-elements, matching the majority of known transcription-factor binding and microRNA targeting sites across diverse species from yeast to human. One of these predicted elements was highly enriched in the earliest zygotically expressed genes in the fly. In collaboration with Eric Wieschaus at Princeton, we experimentally validated the function of this element and identified its transcription-factor partner (DeRenzis et al. PLoS Biology 2007, 5(5):e117). In addition to their value as high-confidence predictions, these comprehensive catalogs are providing unique insights into the evolutionary dynamics of regulatory networks. For example, a large fraction of elements are conserved between flies and worms but they seem to be regulating entirely different sets of genes. This almost complete ‘rewiring’ of the network, yet conservation of the ‘wires’, is a surprising, but seemingly universal characteristic of regulatory network evolution (Elemento and Tavazoie Genome Biology 2005, 6(2):R18; Chan et al. PLoS Comput. Biol. 2005, 1(7): 369).

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