CTCF binding site classes exhibit distinct evolutionary, genomic, epigenomic and transcriptomic features.
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.
Essien
Kobby
K
Penn Center for Bioinformatics, Department of Genetics, 415 Curie Boulevard, University of Pennsylvania, Philadelphia, PA 19104, USA. kobby@pcbi.upenn.edu
Vigneau
Sebastien
S
Apreleva
Sofia
S
Singh
Larry N
LN
Bartolomei
Marisa S
MS
Hannenhalli
Sridhar
S
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
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D006657:Histones; D012097:Repressor Proteins; D004247:DNA