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Nucleic Acids Research 2005 33(17):5437-5445; doi:10.1093/nar/gki853
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Published online 22 September 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
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Article

Human-zebrafish non-coding conserved elements act in vivo to regulate transcription

Jordan T. Shin*, James R. Priest1,2, Ivan Ovcharenko3, Amy Ronco, Rachel K. Moore, C. Geoffrey Burns and Calum A. MacRae

Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School Charlestown, MA 02129, USA 1Genomics Division, Lawrence Berkeley National Laboratory Berkeley, CA 94720, USA 2DOE Joint Genome Institute Walnut Creek, CA 94598, USA 3Lawrence Livermore National Laboratory 7000 East Avenue, Livermore, CA 94550, USA

*To whom correspondence should be addressed. Tel: +1 617 724 9566; Fax: +1 617 726 5806; Email: jshin1{at}partners.org

Received August 4, 2005. Accepted September 5, 2005.

Whole genome comparisons of distantly related species effectively predict biologically important sequences—core genes and cis-acting regulatory elements (REs)—but require experimentation to verify biological activity. To examine the efficacy of comparative genomics in identification of active REs from anonymous, non-coding (NC) sequences, we generated a novel alignment of the human and draft zebrafish genomes, and contrasted this set to existing human and fugu datasets. We tested the transcriptional regulatory potential of candidate sequences using two in vivo assays. Strict selection of non-genic elements which are deeply conserved in vertebrate evolution identifies 1744 core vertebrate REs in human and two fish genomes. We tested 16 elements in vivo for cis-acting gene regulatory properties using zebrafish transient transgenesis and found that 10 (63%) strongly modulate tissue-specific expression of a green fluorescent protein reporter vector. We also report a novel quantitative enhancer assay with potential for increased throughput based on normalized luciferase activity in vivo. This complementary system identified 11 (69%; including 9 of 10 GFP-confirmed elements) with cis-acting function. Together, these data support the utility of comparative genomics of distantly related vertebrate species to identify REs and provide a scaleable, in vivo quantitative assay to define functional activity of candidate REs.

Correspondence may also be addressed to Calum A. MacRae. Tel: +1 617 726 4343; Fax: +1 617 726 5806; Email: cmacrae{at}partners.org

Present address: James R. Priest, Stanford University School of Medicine, Stanford, CA 94305, USA

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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