Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements

Handle URI:
http://hdl.handle.net/10754/599774
Title:
Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements
Authors:
Guturu, H.; Doxey, A. C.; Wenger, A. M.; Bejerano, G.
Abstract:
Mapping the DNA-binding preferences of transcription factor (TF) complexes is critical for deciphering the functions of cis-regulatory elements. Here, we developed a computational method that compares co-occurring motif spacings in conserved versus unconserved regions of the human genome to detect evolutionarily constrained binding sites of rigid TF complexes. Structural data were used to estimate TF complex physical plausibility, explore overlapping motif arrangements seldom tackled by non-structure-aware methods, and generate and analyse three-dimensional models of the predicted complexes bound to DNA. Using this approach, we predicted 422 physically realistic TF complex motifs at 18% false discovery rate, the majority of which (326, 77%) contain some sequence overlap between binding sites. The set of mostly novel complexes is enriched in known composite motifs, predictive of binding site configurations in TF-TF-DNA crystal structures, and supported by ChIP-seq datasets. Structural modelling revealed three cooperativity mechanisms: direct protein-protein interactions, potentially indirect interactions and 'through-DNA' interactions. Indeed, 38% of the predicted complexes were found to contain four or more bases in which TF pairs appear to synergize through overlapping binding to the same DNA base pairs in opposite grooves or strands. Our TF complex and associated binding site predictions are available as a web resource at http://bejerano.stanford.edu/complex.
Citation:
Guturu H, Doxey AC, Wenger AM, Bejerano G (2013) Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements. Philosophical Transactions of the Royal Society B: Biological Sciences 368: 20130029–20130029. Available: http://dx.doi.org/10.1098/rstb.2013.0029.
Publisher:
The Royal Society
Journal:
Philosophical Transactions of the Royal Society B: Biological Sciences
Issue Date:
11-Nov-2013
DOI:
10.1098/rstb.2013.0029
PubMed ID:
24218641
PubMed Central ID:
PMC3826502
Type:
Article
ISSN:
0962-8436; 1471-2970
Sponsors:
H.G. is supported by National Science Foundation Fellowship DGE-1147470. A.C.D. is supported by a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship (PDF). A.M.W. is supported by a Bio-X Stanford Interdisciplinary Graduate Fellowship. G.B. is supported by NIH grants R01HG005058 and R01HD059862 and KAUST. G.B. is a Packard Fellow and Microsoft Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorGuturu, H.en
dc.contributor.authorDoxey, A. C.en
dc.contributor.authorWenger, A. M.en
dc.contributor.authorBejerano, G.en
dc.date.accessioned2016-02-28T06:09:30Zen
dc.date.available2016-02-28T06:09:30Zen
dc.date.issued2013-11-11en
dc.identifier.citationGuturu H, Doxey AC, Wenger AM, Bejerano G (2013) Structure-aided prediction of mammalian transcription factor complexes in conserved non-coding elements. Philosophical Transactions of the Royal Society B: Biological Sciences 368: 20130029–20130029. Available: http://dx.doi.org/10.1098/rstb.2013.0029.en
dc.identifier.issn0962-8436en
dc.identifier.issn1471-2970en
dc.identifier.pmid24218641en
dc.identifier.doi10.1098/rstb.2013.0029en
dc.identifier.urihttp://hdl.handle.net/10754/599774en
dc.description.abstractMapping the DNA-binding preferences of transcription factor (TF) complexes is critical for deciphering the functions of cis-regulatory elements. Here, we developed a computational method that compares co-occurring motif spacings in conserved versus unconserved regions of the human genome to detect evolutionarily constrained binding sites of rigid TF complexes. Structural data were used to estimate TF complex physical plausibility, explore overlapping motif arrangements seldom tackled by non-structure-aware methods, and generate and analyse three-dimensional models of the predicted complexes bound to DNA. Using this approach, we predicted 422 physically realistic TF complex motifs at 18% false discovery rate, the majority of which (326, 77%) contain some sequence overlap between binding sites. The set of mostly novel complexes is enriched in known composite motifs, predictive of binding site configurations in TF-TF-DNA crystal structures, and supported by ChIP-seq datasets. Structural modelling revealed three cooperativity mechanisms: direct protein-protein interactions, potentially indirect interactions and 'through-DNA' interactions. Indeed, 38% of the predicted complexes were found to contain four or more bases in which TF pairs appear to synergize through overlapping binding to the same DNA base pairs in opposite grooves or strands. Our TF complex and associated binding site predictions are available as a web resource at http://bejerano.stanford.edu/complex.en
dc.description.sponsorshipH.G. is supported by National Science Foundation Fellowship DGE-1147470. A.C.D. is supported by a Natural Sciences and Engineering Research Council of Canada Postdoctoral Fellowship (PDF). A.M.W. is supported by a Bio-X Stanford Interdisciplinary Graduate Fellowship. G.B. is supported by NIH grants R01HG005058 and R01HD059862 and KAUST. G.B. is a Packard Fellow and Microsoft Research Fellow. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.en
dc.publisherThe Royal Societyen
dc.subjectComplexesen
dc.subjectTranscription factorsen
dc.subjectCis-regulationen
dc.subjectEnhancersen
dc.subjectCooperative Bindingen
dc.subjectConserved Non-coding Elementsen
dc.subject.meshEvolution, Molecularen
dc.subject.meshModels, Molecularen
dc.titleStructure-aided prediction of mammalian transcription factor complexes in conserved non-coding elementsen
dc.typeArticleen
dc.identifier.journalPhilosophical Transactions of the Royal Society B: Biological Sciencesen
dc.identifier.pmcidPMC3826502en
dc.contributor.institutionDepartment of Electrical Engineering, Stanford University, , Stanford, CA 94305, USA.en

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