Identifying pattern-defined regulatory islands in mammalian genomes.
Identifying cis-regulatory regions in mammalian genomes is a key challenge toward understanding transcriptional regulation. However, identification and functional characterization of those regulatory elements governing differential gene expression has been hampered by the limited understanding of their organization and locations in genomes. We hypothesized that genes that are conserved across species will also display conservation at the level of their transcriptional regulation and that this will be reflected in the organization of cis-elements mediating this regulation. Using a computational approach, clusters of transcription factor binding sites that are absolutely conserved in order and in spacing across human, rat, and mouse genomes were identified. We term these regions pattern-defined regulatory islands (PRIs). We discovered that these sequences are frequently active sites of transcriptional regulation. These PRIs occur in approximately 1.1% of the half-billion base pairs covered in the search and are located mainly in noncoding regions of the genome. We show that the premise of PRIs can be used to identify previously known and novel cis-regulatory regions controlling genes regulated by myogenic differentiation. Thus, PRIs may represent a fundamental property of the architecture of cis-regulatory elements in mammalian genomes, and this feature can be exploited to pinpoint critical transcriptional regulatory elements governing cell type-specific gene expression.
Cheung
Tom H
TH
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Barthel
Kristen K B
KK
Kwan
Yin Lam
YL
Liu
Xuedong
X
D000465:Algorithms; D000818:Animals; D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D017124:Conserved Sequence; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016678:Genome; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008322:Mammals / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012641:Selection, Genetic; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
D014157:Transcription Factors; D008156:Luciferases