31 research outputs found
Motif Discovery through Predictive Modeling of Gene Regulation
We present MEDUSA, an integrative method for learning motif models of
transcription factor binding sites by incorporating promoter sequence and gene
expression data. We use a modern large-margin machine learning approach, based
on boosting, to enable feature selection from the high-dimensional search space
of candidate binding sequences while avoiding overfitting. At each iteration of
the algorithm, MEDUSA builds a motif model whose presence in the promoter
region of a gene, coupled with activity of a regulator in an experiment, is
predictive of differential expression. In this way, we learn motifs that are
functional and predictive of regulatory response rather than motifs that are
simply overrepresented in promoter sequences. Moreover, MEDUSA produces a model
of the transcriptional control logic that can predict the expression of any
gene in the organism, given the sequence of the promoter region of the target
gene and the expression state of a set of known or putative transcription
factors and signaling molecules. Each motif model is either a -length
sequence, a dimer, or a PSSM that is built by agglomerative probabilistic
clustering of sequences with similar boosting loss. By applying MEDUSA to a set
of environmental stress response expression data in yeast, we learn motifs
whose ability to predict differential expression of target genes outperforms
motifs from the TRANSFAC dataset and from a previously published candidate set
of PSSMs. We also show that MEDUSA retrieves many experimentally confirmed
binding sites associated with environmental stress response from the
literature.Comment: RECOMB 200
Treatment-responsive pudendal dysfunction in chronic inflammatory demyelinating polyneuropathy.
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52470.pdf (publisher's version ) (Open Access
Genomewide analysis of Drosophila GAGA factor target genes reveals context-dependent DNA binding.
The association of sequence-specific DNA-binding factors with their cognate target sequences in vivo depends on the local molecular context, yet this context is poorly understood. To address this issue, we have performed genomewide mapping of in vivo target genes of Drosophila GAGA factor (GAF). The resulting list of ≈250 target genes indicates that GAF regulates many cellular pathways. We applied unbiased motif-based regression analysis to identify the sequence context that determines GAF binding. Our results confirm that GAF selectively associates with (GA)(n) repeat elements in vivo. GAF binding occurs in upstream regulatory regions, but less in downstream regions. Surprisingly, GAF binds abundantly to introns but is virtually absent from exons, even though the density of (GA)(n) is roughly the same. Intron binding occurs equally frequently in last introns compared with first introns, suggesting that GAF may not only regulate transcription initiation, but possibly also elongation. We provide evidence for cooperative binding of GAF to closely spaced (GA)(n) elements and explain the lack of GAF binding to exons by the absence of such closely spaced GA repeats. Our approach for revealing determinants of context-dependent DNA binding will be applicable to many other transcription factors