Genome-wide CTCF distribution in vertebrates defines equivalent sites that aid the identification of disease-associated genes

Nat Struct Mol Biol. 2011 Jun;18(6):708-14. doi: 10.1038/nsmb.2059. Epub 2011 May 22.


Many genomic alterations associated with human diseases localize in noncoding regulatory elements located far from the promoters they regulate, making it challenging to link noncoding mutations or risk-associated variants with target genes. The range of action of a given set of enhancers is thought to be defined by insulator elements bound by the 11 zinc-finger nuclear factor CCCTC-binding protein (CTCF). Here we analyzed the genomic distribution of CTCF in various human, mouse and chicken cell types, demonstrating the existence of evolutionarily conserved CTCF-bound sites beyond mammals. These sites preferentially flank transcription factor-encoding genes, often associated with human diseases, and function as enhancer blockers in vivo, suggesting that they act as evolutionarily invariant gene boundaries. We then applied this concept to predict and functionally demonstrate that the polymorphic variants associated with multiple sclerosis located within the EVI5 gene impinge on the adjacent gene GFI1.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor
  • Cell Cycle Proteins
  • Cell Line
  • Chickens
  • Conserved Sequence
  • DNA / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • GTPase-Activating Proteins
  • Genome*
  • Humans
  • Mice
  • Multiple Sclerosis / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polymorphism, Genetic
  • Protein Binding
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Cell Cycle Proteins
  • Ctcf protein, mouse
  • DNA-Binding Proteins
  • EVI5 protein, human
  • GFI1 protein, human
  • GTPase-Activating Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Transcription Factors
  • DNA