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Constitutively bound CTCF sites maintain 3D chromatin architecture and long-range epigenetically regulated domains

Author

Listed:
  • Amanda Khoury

    (Garvan Institute of Medical Research)

  • Joanna Achinger-Kawecka

    (Garvan Institute of Medical Research)

  • Saul A. Bert

    (Garvan Institute of Medical Research)

  • Grady C. Smith

    (Garvan Institute of Medical Research)

  • Hugh J. French

    (Garvan Institute of Medical Research)

  • Phuc-Loi Luu

    (Garvan Institute of Medical Research)

  • Timothy J. Peters

    (Garvan Institute of Medical Research)

  • Qian Du

    (Garvan Institute of Medical Research)

  • Aled J. Parry

    (Garvan Institute of Medical Research)

  • Fatima Valdes-Mora

    (Garvan Institute of Medical Research)

  • Phillippa C. Taberlay

    (Garvan Institute of Medical Research
    University of Tasmania)

  • Clare Stirzaker

    (Garvan Institute of Medical Research
    UNSW Sydney)

  • Aaron L. Statham

    (Garvan Institute of Medical Research)

  • Susan J. Clark

    (Garvan Institute of Medical Research
    UNSW Sydney)

Abstract

The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is orchestrated to maintain long-range gene expression is poorly understood. Here we perform RNAi knockdown to reduce CTCF levels and reveal a shared subset of CTCF-bound sites are robustly resistant to protein depletion. The ‘persistent’ CTCF sites are enriched at domain boundaries and chromatin loops constitutive to all cell types. CRISPR-Cas9 deletion of 2 persistent CTCF sites at the boundary between a long-range epigenetically active (LREA) and silenced (LRES) region, within the Kallikrein (KLK) locus, results in concordant activation of all 8 KLK genes within the LRES region. CTCF genome-wide depletion results in alteration in Topologically Associating Domain (TAD) structure, including the merging of TADs, whereas TAD boundaries are not altered where persistent sites are maintained. We propose that the subset of essential CTCF sites are involved in cell-type constitutive, higher order chromatin architecture.

Suggested Citation

  • Amanda Khoury & Joanna Achinger-Kawecka & Saul A. Bert & Grady C. Smith & Hugh J. French & Phuc-Loi Luu & Timothy J. Peters & Qian Du & Aled J. Parry & Fatima Valdes-Mora & Phillippa C. Taberlay & Cla, 2020. "Constitutively bound CTCF sites maintain 3D chromatin architecture and long-range epigenetically regulated domains," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-13753-7
    DOI: 10.1038/s41467-019-13753-7
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    Cited by:

    1. Ariane Lismer & Sarah Kimmins, 2023. "Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Julia Minderjahn & Alexander Fischer & Konstantin Maier & Karina Mendes & Margit Nuetzel & Johanna Raithel & Hanna Stanewsky & Ute Ackermann & Robert Månsson & Claudia Gebhard & Michael Rehli, 2022. "Postmitotic differentiation of human monocytes requires cohesin-structured chromatin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Kevin B. Dsouza & Alexandra Maslova & Ediem Al-Jibury & Matthias Merkenschlager & Vijay K. Bhargava & Maxwell W. Libbrecht, 2022. "Learning representations of chromatin contacts using a recurrent neural network identifies genomic drivers of conformation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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