Columbia University in the City of New York

Tavazoie Lab

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).

Related publications

Coupling of zygotic transcription to mitotic control at the Drosophila mid-blastula transition.
Development. 2009 Jun;136(12):2101-10. PDF
Lu X, Li JM, Elemento O, Tavazoie S, Wieschaus EF

let-7 Overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34, and stabilization of Wee1 kinase in primary fibroblasts.
J Biol Chem. 2009 Mar 13;284(11):6605-9. Epub 2009 Jan 6. PDF
Legesse-Miller A, Elemento O, Pfau SJ, Forman JJ, Tavazoie S, Coller HA

A universal framework for regulatory element discovery across all genomes and data-types
Molecular Cell (2007) 28(2):337-50 PDF
Elemento O, Slonim N, Tavazoie S

Unmasking the zygotic genome using chromosome deletion in the Drosophila embryo.
PLoS Biology (2007) 5(5): e117. PDF
De Renzis S, Elemento O, Tavazoie S, Wieschaus EF

Fastcompare: A non-alignment approach for genome-scale discovery of DNA and mRNA regulatory elements using network-level conservation
Methods in Mol. Biol., Comparative Genomics, 2007
Elemento O, Tavazoie S.

Revealing posttranscriptional regulatory elements through network-level conservation.
PLoS Computational Biology 2005 Dec; 1(7): e69 Epub 2005 Dec. 9. PDF
(Chan S, Elemento O, equal contribution) and Tavazoie S

Fast and systematic genome-wide discovery of conserved regulatory elements using a non-alignment based approach.
Genome Biology (2005) 6(2):R18. Epub 2005 Jan 26. PDF
Elemento O, Tavazoie S

Whole-genome discovery of transcription factor binding sites by network-level conservation.
Genome Research 2004 Jan; 14(1):99-108. PDF
Pritsker M, Liu Y, Beer M, Tavazoie S

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