title: Functional diversity of CTCFs is encoded in their binding motifs.
abstract: BACKGROUND
  The CCCTC-binding factor (CTCF) has diverse regulatory functions. However, the definitive characteristics of the CTCF binding motif required for its functional diversity still remains elusive.
  
  
  RESULTS
  Here, we describe a new motif discovery workflow by which we have identified three CTCF binding motif variations with highly divergent functionalities. Supported by transcriptomic, epigenomic and chromatin-interactomic data, we show that the functional diversity of the CTCF binding motifs is strongly associated with their GC content, CpG dinucleotide coverage and relative DNA methylation level at the 12th position of the motifs. Further analysis suggested that the co-localization of cohesin, the key factor in cohesion of sister chromatids, is negatively correlated with the CpG coverage and the relative DNA methylation level at the 12th position. Finally, we present evidences for a hypothetical model in which chromatin interactions between promoters and distal regulatory regions are likely mediated by CTCFs binding to sequences with high CpG.
  
  
  CONCLUSIONS
  These results demonstrate the existence of definitive CTCF binding motifs corresponding to CTCF's diverse functions, and that the functional diversity of the motifs is strongly associated with genetic and epigenetic features at the 12th position of the motifs.
authors: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. r3fang@eng.ucsd.edu.
authors: Rongxin
authors: R
authors: Fang
authors: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. charleywangcq@gmail.com.
authors: Chengqi
authors: C
authors: Wang
authors: Bioinformatics Laboratory and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. geirsk2000@yahoo.com.
authors: Geir
authors: G
authors: Skogerbo
authors: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, 100101, China. zhangzhihua@big.ac.cn.
authors: Zhihua
authors: Z
authors: Zhang
mesh_terms: D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics*; D011485:Protein Binding; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins