title: Motif oriented high-resolution analysis of ChIP-seq data reveals the topological order of CTCF and cohesin proteins on DNA.
abstract: ChIP-seq provides a wealth of information on the approximate location of DNA-binding proteins genome-wide. It is known that the targeted motifs in most cases can be found at the peak centers. A high resolution mapping of ChIP-seq peaks could in principle allow the fine mapping of the protein constituents within protein complexes, but the current ChIP-seq analysis pipelines do not target the basepair resolution strand specific mapping of peak summits.
  
  
  
  The approach proposed here is based on i) locating regions that are bound by a sufficient number of proteins constituting a complex; ii) determining the position of the underlying motif using either a direct or a de novo motif search approach; and iii) determining the exact location of the peak summits with respect to the binding motif in a strand specific manner. We applied this method for analyzing the CTCF/cohesin complex, which holds together DNA loops. The relative positions of the constituents of the complex were determined with one-basepair estimated accuracy. Mapping the positions on a 3D model of DNA made it possible to deduce the approximate local topology of the complex that allowed us to predict how the CTCF/cohesin complex locks the DNA loops. As the positioning of the proteins was not compatible with previous models of loop closure, we proposed a plausible "double embrace" model in which the DNA loop is held together by two adjacent cohesin rings in such a way that the ring anchored by CTCF to one DNA duplex encircles the other DNA double helix and vice versa.
  
  
  
  A motif-centered, strand specific analysis of ChIP-seq data improves the accuracy of determining peak positions. If a genome contains a large number of binding sites for a given protein complex, such as transcription factor heterodimers or transcription factor/cofactor complexes, the relative position of the constituent proteins on the DNA can be established with an accuracy that allow one to deduce the local topology of the protein complex. The proposed high resolution mapping approach of ChIP-seq data is applicable for detecting the contact topology of DNA-binding protein complexes.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032, Hungary.|MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Gergely
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: Erik
authors.initials: E
authors.lastname: Czipa
authors.affiliation: UD-GenoMed Medical Genomic Technologies Research & Development Services Ltd., Nagyerdei krt. 98., Debrecen, H-4032, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Steiner
authors.affiliation: Agricultural Genomics and Bioinformatics Group, Agricultural Biotechnology Institute, NARIC, Gödöllő, H-2100, Hungary.|Present address: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors.forename: Tibor
authors.initials: T
authors.lastname: Nagy
authors.affiliation: Faculty of Information Technology and Bionics, Pázmány Péter Catholic University Budapest H-1083, Gödöllő, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Pongor
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032, Hungary.|MTA-DE Lendület Immunogenomics Research Group, University of Debrecen, Debrecen, H-4032, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Nagy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, H-4032, Hungary. barta.endre@unideb.hu.|Agricultural Genomics and Bioinformatics Group, Agricultural Biotechnology Institute, NARIC, Gödöllő, H-2100, Hungary. barta.endre@unideb.hu.
authors.forename: Endre
authors.identifier: 0000-0002-6753-0714
authors.initials: E
authors.lastname: Barta
mesh_terms: D000818:Animals; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000097722:Cohesins; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse
keywords: CTCF; ChIP-seq; DNA loop; cohesin