Binding site discovery from nucleic acid sequences by discriminative learning of hidden Markov models.
We present a discriminative learning method for pattern discovery of binding sites in nucleic acid sequences based on hidden Markov models. Sets of positive and negative example sequences are mined for sequence motifs whose occurrence frequency varies between the sets. The method offers several objective functions, but we concentrate on mutual information of condition and motif occurrence. We perform a systematic comparison of our method and numerous published motif-finding tools. Our method achieves the highest motif discovery performance, while being faster than most published methods. We present case studies of data from various technologies, including ChIP-Seq, RIP-Chip and PAR-CLIP, of embryonic stem cell transcription factors and of RNA-binding proteins, demonstrating practicality and utility of the method. For the alternative splicing factor RBM10, our analysis finds motifs known to be splicing-relevant. The motif discovery method is implemented in the free software package Discrover. It is applicable to genome- and transcriptome-scale data, makes use of available repeat experiments and aside from binary contrasts also more complex data configurations can be utilized.
Laboratory for Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch 13125, Germany jonas@maaskola.de.
Jonas
J
Maaskola
Laboratory for Systems Biology of Gene Regulatory Elements, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin-Buch 13125, Germany.
Nikolaus
N
Rajewsky
D000818:Animals; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D006801:Humans; D008390:Markov Chains; D051379:Mice; D059372:Nucleotide Motifs; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017422:Sequence Analysis, DNA / Q000379:methods*; D017423:Sequence Analysis, RNA / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors