Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries

Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; pp. 5615 - 19
Main Authors:	Chang, Li-Hsin, Ghosh, Sourav, Papale, Andrea, Luppino, Jennifer M., Miranda, Mélanie, Piras, Vincent, Degrouard, Jéril, Edouard, Joanne, Poncelet, Mallory, Lecouvreur, Nathan, Bloyer, Sébastien, Leforestier, Amélie, Joyce, Eric F., Holcman, David, Noordermeer, Daan
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 12-09-2023 Nature Publishing Group Nature Portfolio
Subjects:	14/32 45/100 45/15 45/71 45/77 45/88 45/91 631/337/100/101 631/337/386 631/337/572/2102 Binding Sites Biochemistry, Molecular Biology Boundaries CCCTC-Binding Factor - genetics Cluster Analysis Clustering Cohesin CTCF protein Extrusion Genomes Genomics Humanities and Social Sciences Insulation Life Sciences multidisciplinary Protein Domains Proteins Science Science (multidisciplinary) Vertebrates
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs. Most mammalian TAD boundaries, which separate functional chromosomal domains, bind the CTCF protein. Here, the authors identify multi-level clustering of CTCF binding sites at TAD boundaries and confirm their individual contribution to TAD formation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-41265-y