Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation

Xiao Ge, Haiyan Huang, Keqi Han, Wangjie Xu, Zhaoxia Wang and Qiang Wu ()
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Xiao Ge: Shanghai Jiao Tong University
Haiyan Huang: Shanghai Jiao Tong University
Keqi Han: Shanghai Jiao Tong University
Wangjie Xu: Shanghai Jiao Tong University
Zhaoxia Wang: Shanghai Jiao Tong University
Qiang Wu: Shanghai Jiao Tong University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract CTCF plays an important role in 3D genome organization by adjusting the strength of chromatin insulation at TAD boundaries, where clustered CBS (CTCF-binding site) elements are often arranged in a tandem array with a complex divergent or convergent orientation. Here, using Pcdh and HOXD loci as a paradigm, we look into the clustered CTCF TAD boundaries and find that, counterintuitively, outward-oriented CBS elements are crucial for inward enhancer-promoter interactions as well as for gene regulation. Specifically, by combinatorial deletions of a series of putative enhancer elements in mice in vivo or CBS elements in cultured cells in vitro, in conjunction with chromosome conformation capture and RNA-seq analyses, we show that deletions of outward-oriented CBS elements weaken the strength of long-distance intra-TAD promoter-enhancer interactions and enhancer activation of target genes. Our data highlight the crucial role of outward-oriented CBS elements within the clustered CTCF TAD boundaries in developmental gene regulation and have interesting implications on the organization principles of clustered CTCF sites within TAD boundaries.

Date: 2023
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DOI: 10.1038/s41467-023-43849-0

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