A Genome-wide Map of CTCF Multivalency Redefines the CTCF Code

Hirotaka Nakahashi, Kyong Rim Kieffer Kwon, Wolfgang Resch, Laura Vian, Marei Dose, Diana Stavreva, Ofir Hakim, Nathanael Pruett, Steevenson Nelson, Arito Yamane, Jason Qian, Wendy Dubois, Scott Welsh, Robert D. Phair, B. Franklin Pugh, Victor Lobanenkov, Gordon L. Hager, Rafael Casellas

Research output: Contribution to journalArticlepeer-review

213 Scopus citations


The "CTCF code" hypothesis posits that CTCF pleiotropic functions are driven by recognition of diverse sequences through combinatorial use of its 11 zinc fingers (ZFs). This model, however, is supported by invitro binding studies of a limited number of sequences. To study CTCF multivalency invivo, we define ZF binding requirements at ~50,000 genomic sites in primary lymphocytes. We find that CTCF reads sequence diversity through ZF clustering. ZFs 4-7 anchor CTCF to ~80% of targets containing the core motif. Nonconserved flanking sequences are recognized by ZFs 1-2 and ZFs 8-11 clusters, which also stabilize CTCF broadly. Alternatively, ZFs 9-11 associate with a second phylogenetically conserved upstream motif at ~15% of its sites. Individually, ZFs increase overall binding and chromatin residence time. Unexpectedly, we also uncovered a conserved downstream DNA motif that destabilizes CTCF occupancy. Thus, CTCF associates with a wide array of DNA modules via combinatorial clustering of its 11 ZFs.

Original languageEnglish
Pages (from-to)1678-1689
Number of pages12
JournalCell Reports
Issue number5
StatePublished - 30 May 2013

Bibliographical note

Funding Information:
We thank G. Gutierrez from the NIAMS genomics facility for technical assistance and Ethan Tyler for designing Figure 7 C. This work was supported in part by the Intramural Research Program of NIAMS and NCI, NIH. The study made use of the high-performance computational capabilities of the Biowulf Linux cluster at the NIH ( http://biowulf.nih.gov ) and the resources of NCI’s High-Throughput Imaging Facility. L.V. was supported in part by an American-Italian Cancer Foundation postdoctoral research fellowship.


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