title: CTCF binding site classes exhibit distinct evolutionary, genomic, epigenomic and transcriptomic features.
abstract: BACKGROUND
  CTCF (CCCTC-binding factor) is an evolutionarily conserved zinc finger protein involved in diverse functions ranging from negative regulation of MYC, to chromatin insulation of the beta-globin gene cluster, to imprinting of the Igf2 locus. The 11 zinc fingers of CTCF are known to differentially contribute to the CTCF-DNA interaction at different binding sites. It is possible that the differences in CTCF-DNA conformation at different binding sites underlie CTCF's functional diversity. If so, the CTCF binding sites may belong to distinct classes, each compatible with a specific functional role.
  
  
  RESULTS
  We have classified approximately 26,000 CTCF binding sites in CD4+ T cells into three classes based on their similarity to the well-characterized CTCF DNA-binding motif. We have comprehensively characterized these three classes of CTCF sites with respect to several evolutionary, genomic, epigenomic, transcriptomic and functional features. We find that the low-occupancy sites tend to be cell type specific. Furthermore, while the high-occupancy sites associate with repressive histone marks and greater gene co-expression within a CTCF-flanked block, the low-occupancy sites associate with active histone marks and higher gene expression. We found that the low-occupancy sites have greater conservation in their flanking regions compared to high-occupancy sites. Interestingly, based on a novel class-conservation metric, we observed that human low-occupancy sites tend to be conserved as low-occupancy sites in mouse (and vice versa) more frequently than expected.
  
  
  CONCLUSIONS
  Our work reveals several key differences among CTCF occupancy-based classes and suggests a critical, yet distinct functional role played by low-occupancy sites.
authors.affiliation: Penn Center for Bioinformatics, Department of Genetics, 415 Curie Boulevard, University of Pennsylvania, Philadelphia, PA 19104, USA. kobby@pcbi.upenn.edu
authors.forename: Kobby
authors.initials: K
authors.lastname: Essien
authors.forename: Sebastien
authors.initials: S
authors.lastname: Vigneau
authors.forename: Sofia
authors.initials: S
authors.lastname: Apreleva
authors.forename: Larry N
authors.initials: LN
authors.lastname: Singh
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Bartolomei
authors.forename: Sridhar
authors.initials: S
authors.lastname: Hannenhalli
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D000076246:CCCTC-Binding Factor; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D004247:DNA / Q000235:genetics; D044127:Epigenesis, Genetic; D019143:Evolution, Molecular; D023281:Genomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008957:Models, Genetic; D005810:Multigene Family; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D006657:Histones; D012097:Repressor Proteins; D004247:DNA