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Molecular basis of CTCF binding polarity in genome folding

Author

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  • Elphège P. Nora

    (Gladstone Institutes
    Roddenberry Center for Stem Cell Biology and Medicine at Gladstone
    Cardiovascular Research Institute, University of California San Francisco
    University of California San Francisco)

  • Laura Caccianini

    (Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168)

  • Geoffrey Fudenberg

    (Gladstone Institutes)

  • Kevin So

    (Gladstone Institutes)

  • Vasumathi Kameswaran

    (Gladstone Institutes
    Roddenberry Center for Stem Cell Biology and Medicine at Gladstone)

  • Abigail Nagle

    (Gladstone Institutes
    University of Washington)

  • Alec Uebersohn

    (Gladstone Institutes
    University of California Berkeley)

  • Bassam Hajj

    (Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168)

  • Agnès Le Saux

    (Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Mammalian Developmental Epigenetics group
    Sorbonne Université)

  • Antoine Coulon

    (Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168
    Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR3664, Nuclear Dynamics unit)

  • Leonid A. Mirny

    (Institute for Medical Engineering and Science and Department of Physics, Massachusetts Institute of Technology)

  • Katherine S. Pollard

    (Gladstone Institutes
    Institute for Human Genetics, Quantitative Biology Institute, and Institute for Computational Health Sciences, University of California San Francisco
    Chan Zuckerberg Biohub)

  • Maxime Dahan

    (Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168)

  • Benoit G. Bruneau

    (Gladstone Institutes
    Roddenberry Center for Stem Cell Biology and Medicine at Gladstone
    Cardiovascular Research Institute, University of California San Francisco
    University of California San Francisco)

Abstract

Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns.

Suggested Citation

  • Elphège P. Nora & Laura Caccianini & Geoffrey Fudenberg & Kevin So & Vasumathi Kameswaran & Abigail Nagle & Alec Uebersohn & Bassam Hajj & Agnès Le Saux & Antoine Coulon & Leonid A. Mirny & Katherine , 2020. "Molecular basis of CTCF binding polarity in genome folding," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19283-x
    DOI: 10.1038/s41467-020-19283-x
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    Cited by:

    1. Jingxuan Xu & Xiang Xu & Dandan Huang & Yawen Luo & Lin Lin & Xuemei Bai & Yang Zheng & Qian Yang & Yu Cheng & An Huang & Jingyi Shi & Xiaochen Bo & Jin Gu & Hebing Chen, 2024. "A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Ryuichiro Nakato & Toyonori Sakata & Jiankang Wang & Luis Augusto Eijy Nagai & Yuya Nagaoka & Gina Miku Oba & Masashige Bando & Katsuhiko Shirahige, 2023. "Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Marko Dunjić & Felix Jonas & Gilad Yaakov & Roye More & Yoav Mayshar & Yoach Rais & Ayelet-Hashahar Orenbuch & Saifeng Cheng & Naama Barkai & Yonatan Stelzer, 2023. "Histone exchange sensors reveal variant specific dynamics in mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Li-Hsin Chang & Sourav Ghosh & Andrea Papale & Jennifer M. Luppino & Mélanie Miranda & Vincent Piras & Jéril Degrouard & Joanne Edouard & Mallory Poncelet & Nathan Lecouvreur & Sébastien Bloyer & Amél, 2023. "Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Jia-Yong Zhong & Longjian Niu & Zhuo-Bin Lin & Xin Bai & Ying Chen & Feng Luo & Chunhui Hou & Chuan-Le Xiao, 2023. "High-throughput Pore-C reveals the single-allele topology and cell type-specificity of 3D genome folding," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Yufan Zhou & Tian Li & Lavanya Choppavarapu & Kun Fang & Shili Lin & Victor X. Jin, 2024. "Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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