TY - JOUR
T1 - CTCF binding site sequence differences are associated with unique regulatory and functional trends during embryonic stem cell differentiation
AU - Plasschaert, Robert N.
AU - Vigneau, Sébastien
AU - Tempera, Italo
AU - Gupta, Ravi
AU - Maksimoska, Jasna
AU - Everett, Logan
AU - Davuluri, Ramana
AU - Mamorstein, Ronen
AU - Lieberman, Paul M.
AU - Schultz, David
AU - Hannenhalli, Sridhar
AU - Bartolomei, Marisa S.
N1 - Funding Information:
NIH [R01HD042026 to M.S.B., R01CA140652 to P.M.L., R01GM085226 to S.H., R01-GM052880 to R.M., K99AI099153 to I.T.]; the Wistar Cancer Center core grant [P30 CA10815]; the Commonwealth Universal Research Enhancement Program, PA Department of Health; a postdoctoral fellowship from the American Heart Association (to S.V.); [T32GM008216 to R.P.]. Funding for open access charge: NIH
PY - 2014/1/1
Y1 - 2014/1/1
N2 - CTCF (CCCTC-binding factor) is a highly conservedmultifunctional DNA-binding protein with thousands of binding sites genome-wide. Our previous work suggested that differences in CTCF's binding site sequence may affect the regulation of CTCF recruitment and its function. To investigate this possibility, we characterized changes in genome-wide CTCF binding and gene expression during differentiation of mouse embryonic stem cells. After separating CTCF sites into three classes (LowOc, MedOc and HighOc) based on similarity to the consensus motif, we found that developmentally regulated CTCF binding occurs preferentially at LowOc sites, which have lower similarity to the consensus. By measuring the affinity of CTCF for selected sites, we show that sites lost during differentiation are enriched in motifs associated with weaker CTCF binding in vitro. Specifically, enrichment for T at the 18th position of the CTCF binding site is associated with regulated binding in the LowOc class and can predictably reduce CTCF affinity for binding sites. Finally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. Our results suggest that the regulatory control of CTCF is dependent in part on specific motifs within its binding site.
AB - CTCF (CCCTC-binding factor) is a highly conservedmultifunctional DNA-binding protein with thousands of binding sites genome-wide. Our previous work suggested that differences in CTCF's binding site sequence may affect the regulation of CTCF recruitment and its function. To investigate this possibility, we characterized changes in genome-wide CTCF binding and gene expression during differentiation of mouse embryonic stem cells. After separating CTCF sites into three classes (LowOc, MedOc and HighOc) based on similarity to the consensus motif, we found that developmentally regulated CTCF binding occurs preferentially at LowOc sites, which have lower similarity to the consensus. By measuring the affinity of CTCF for selected sites, we show that sites lost during differentiation are enriched in motifs associated with weaker CTCF binding in vitro. Specifically, enrichment for T at the 18th position of the CTCF binding site is associated with regulated binding in the LowOc class and can predictably reduce CTCF affinity for binding sites. Finally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. Our results suggest that the regulatory control of CTCF is dependent in part on specific motifs within its binding site.
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U2 - 10.1093/nar/gkt910
DO - 10.1093/nar/gkt910
M3 - Article
C2 - 24121688
AN - SCOPUS:84893315198
SN - 0305-1048
VL - 42
SP - 774
EP - 789
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 2
ER -