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

doi:10.1016/j.celrep.2013.04.024

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

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

228 Scopus citations

Abstract

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 language	English
Pages (from-to)	1678-1689
Number of pages	12
Journal	Cell Reports
Volume	3
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2013.04.024
State	Published - 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.

Funding

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.

Funders	Funder number
National Institutes of Health
National Cancer Institute	ZIABC010027
National Institute of Arthritis and Musculoskeletal and Skin Diseases
American-Italian Cancer Foundation

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10.1016/j.celrep.2013.04.024

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Nakahashi, H., Kwon, K. R. K., Resch, W., Vian, L., Dose, M., Stavreva, D., Hakim, O., Pruett, N., Nelson, S., Yamane, A., Qian, J., Dubois, W., Welsh, S., Phair, R. D., Pugh, B. F., Lobanenkov, V., Hager, G. L., & Casellas, R. (2013). A Genome-wide Map of CTCF Multivalency Redefines the CTCF Code. Cell Reports, 3(5), 1678-1689. https://doi.org/10.1016/j.celrep.2013.04.024

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abstract = "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.",

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

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{\textquoteright}s High-Throughput Imaging Facility. L.V. was supported in part by an American-Italian Cancer Foundation postdoctoral research fellowship. ",

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AU - Dose, Marei

AU - Stavreva, Diana

AU - Hakim, Ofir

AU - Pruett, Nathanael

AU - Nelson, Steevenson

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AU - Qian, Jason

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

Abstract

Bibliographical note

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