Cross-species de novo identification of cis-regulatory modules with GibbsModule: application to gene regulation in embryonic stem cells.
We introduce the GibbsModule algorithm for de novo detection of cis-regulatory motifs and modules in eukaryote genomes. GibbsModule models the coexpressed genes within one species as sharing a core cis-regulatory motif and each homologous gene group as sharing a homologous cis-regulatory module (CRM), characterized by a similar composition of motifs. Without using a predetermined alignment result, GibbsModule iteratively updates the core motif shared by coexpressed genes and traces the homologous CRMs that contain the core motif. GibbsModule achieved substantial improvements in both precision and recall as compared with peer algorithms on a number of synthetic and real data sets. Applying GibbsModule to analyze the binding regions of the Krüppel-like factor (KLF) transcription factor in embryonic stem cells (ESCs), we discovered a motif that differs from a previously published KLF motif identified by a SELEX experiment, but the new motif is consistent with mutagenesis analysis. The SOX2 motif was found to be a collaborating motif to the KLF motif in ESCs. We used quantitative chromatin immunoprecipitation (ChIP) analysis to test whether GibbsModule could distinguish functional and nonfunctional binding sites. All seven tested binding sites in GibbsModule-predicted CRMs had higher ChIP signals as compared with the other seven tested binding sites located outside of predicted CRMs. GibbsModule is available at (http://biocomp.bioen.uiuc.edu/GibbsModule).
Xie
Dan
D
Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Cai
Jun
J
Chia
Na-Yu
NY
Ng
Huck H
HH
Zhong
Sheng
S
D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D023281:Genomics; D024002:HMGB Proteins / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D024002:HMGB Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors