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

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, Clare Stirzaker, Aaron L. Statham and Susan J. Clark ()
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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
Clare Stirzaker: Garvan Institute of Medical Research
Aaron L. Statham: Garvan Institute of Medical Research
Susan J. Clark: Garvan Institute of Medical Research

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13753-7

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