title: ConBind: motif-aware cross-species alignment for the identification of functional transcription factor binding sites.
abstract: Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides. This approach might result in the omission of conserved motifs that contain interchangeable nucleotides such as the ETS motif (IUPAC code: GGAW). Here, we introduce ConBind, a novel method to enhance alignment of short motifs, even if their mutual sequence similarity is only partial. ConBind improves the identification of conserved TFBSs by improving the alignment accuracy of TFBS families within orthologous DNA sequences. Functional validation of the Gfi1b + 13 enhancer reveals that ConBind identifies additional functionally important ETS binding sites that were missed by all other tested alignment tools. In addition to the analysis of known regulatory regions, our web tool is useful for the analysis of TFBSs on so far unknown DNA regions identified through ChIP-sequencing.
authors.affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Lelieveld
authors.affiliation: Department of Haematology, Wellcome Trust-MRC Cambridge Stem Cell Institute & Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 0XY, UK Klinik für Hämatologie, Universitätsklinik Essen 45147, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Schütte
authors.affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands.
authors.forename: Maurits J J
authors.initials: MJ
authors.lastname: Dijkstra
authors.affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands.
authors.forename: Punto
authors.initials: P
authors.lastname: Bawono
authors.affiliation: Department of Haematology, Wellcome Trust-MRC Cambridge Stem Cell Institute & Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 0XY, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Kinston
authors.affiliation: Department of Haematology, Wellcome Trust-MRC Cambridge Stem Cell Institute & Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 0XY, UK bg200@cam.ac.uk.
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands j.heringa@vu.nl.
authors.forename: Jaap
authors.initials: J
authors.lastname: Heringa
authors.affiliation: Centre for Integrative Bioinformatics VU, VU University Amsterdam, Amsterdam 1081 HV, The Netherlands Computational Cancer Biology Group, Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands ENPICOM, Eindhoven 5632 CW, The Netherlands n.bonzanni@vu.nl.
authors.forename: Nicola
authors.identifier: 0000-0003-4412-880X
authors.initials: N
authors.lastname: Bonzanni
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors