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

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.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Khoury, A.; Achinger-Kawecka, J.; Bert, S. A.; Smith, G. C.; French, H. J.; Luu, P. L.; Peters, T. J.; Du, Q.; Parry, A. J.; Valdes-Mora, F.; Taberlay, P. C.; Stirzaker, C.; Statham, A. L.; Clark, S. J.
Responsible Garvan Author Prof Susan Clark
Publisher Name Nature Communications
Published Date 2020-01-07
Published Volume 11
Published Issue 1
Published Pages 54
Status Published in-print
DOI 10.1038/s41467-019-13753-7
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/31911579