Human-mouse genome comparisons to locate regulatory sites.
Elucidating the human transcriptional regulatory network is a challenge of the post-genomic era. Technical progress so far is impressive, including detailed understanding of regulatory mechanisms for at least a few genes in multicellular organisms, rapid and precise localization of regulatory regions within extensive regions of DNA by means of cross-species comparison, and de novo determination of transcription-factor binding specificities from large-scale yeast expression data. Here we address two problems involved in extending these results to the human genome: first, it has been unclear how many model organism genomes will be needed to delineate most regulatory regions; and second, the discovery of transcription-factor binding sites (response elements) from expression data has not yet been generalized from single-celled organisms to multicellular organisms. We found that 98% (74/75) of experimentally defined sequence-specific binding sites of skeletal-muscle-specific transcription factors are confined to the 19% of human sequences that are most conserved in the orthologous rodent sequences. Also we found that in using this restriction, the binding specificities of all three major muscle-specific transcription factors (MYF, SRF and MEF2) can be computationally identified.
Wasserman
W W
WW
Bioinformatics Group, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Palumbo
M
M
Thompson
W
W
Fickett
J W
JW
Lawrence
C E
CE
D000465:Algorithms; D000818:Animals; D001483:Base Sequence; D016384:Consensus Sequence; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D051379:Mice / Q000235:genetics*; D008957:Models, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D016415:Sequence Alignment; D014158:Transcription, Genetic