Motif-blind, genome-wide discovery of cis-regulatory modules in Drosophila and mouse.
We present new approaches to cis-regulatory module (CRM) discovery in the common scenario where relevant transcription factors and/or motifs are unknown. Beginning with a small list of CRMs mediating a common gene expression pattern, we search genome-wide for CRMs with similar functionality, using new statistical scores and without requiring known motifs or accurate motif discovery. We cross-validate our predictions on 31 regulatory networks in Drosophila and through correlations with gene expression data. Five predicted modules tested using an in vivo reporter gene assay all show tissue-specific regulatory activity. We also demonstrate our methods' ability to predict mammalian tissue-specific enhancers. Finally, we predict human CRMs that regulate early blood and cardiovascular development. In vivo transgenic mouse analysis of two predicted CRMs demonstrates that both have appropriate enhancer activity. Overall, 7/7 predictions were validated successfully in vivo, demonstrating the effectiveness of our approach for insect and mammalian genomes.
Kantorovitz
Miriam R
MR
Department of Mathematics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Kazemian
Majid
M
Kinston
Sarah
S
Miranda-Saavedra
Diego
D
Zhu
Qiyun
Q
Robinson
Gene E
GE
Göttgens
Berthold
B
Halfon
Marc S
MS
Sinha
Saurabh
S
D000465:Algorithms; D000818:Animals; D030801:Animals, Genetically Modified; D019295:Computational Biology; D004330:Drosophila / Q000196:embryology / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D016678:Genome; D006321:Heart / Q000196:embryology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D051379:Mice / Q000196:embryology / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D013045:Species Specificity; D014157:Transcription Factors / Q000235:genetics
D014157:Transcription Factors