Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity.
Understanding the regulation of human gene expression requires knowledge of the "second genetic code," which consists of the binding specificities of transcription factors (TFs) and the combinatorial code by which TF binding sites are assembled to form tissue-specific enhancer elements. Using a novel high-throughput method, we determined the DNA binding specificities of GLIs 1-3, Tcf4, and c-Ets1, which mediate transcriptional responses to the Hedgehog (Hh), Wnt, and Ras/MAPK signaling pathways. To identify mammalian enhancer elements regulated by these pathways on a genomic scale, we developed a computational tool, enhancer element locator (EEL). We show that EEL can be used to identify Hh and Wnt target genes and to predict activated TFs based on changes in gene expression. Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes.
Hallikas
Outi
O
Molecular and Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland.
Palin
Kimmo
K
Sinjushina
Natalia
N
Rautiainen
Reetta
R
Partanen
Juha
J
Ukkonen
Esko
E
Taipale
Jussi
J
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002645:Chickens; D019295:Computational Biology / Q000379:methods; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D016259:Genes, myc / Q000502:physiology; D016678:Genome; D053823:Hedgehog Proteins; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D023721:Tetraodontiformes; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D029721:Drosophila Proteins; C117596:HHIP protein, human; D053823:Hedgehog Proteins; C498447:Hhip protein, mouse; D008562:Membrane Glycoproteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; C077245:hh protein, Drosophila