Title: Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver.
Authors: Matthews, Bryan J; Waxman, David J
Published In Elife, (2018 05 14)
Abstract: CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that intra-TAD loops form by the same loop extrusion mechanism as the larger TAD loops, and that their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.
PubMed ID: 29757144
MeSH Terms: Animals; Binding Sites; CCCTC-Binding Factor/metabolism*; Cell Cycle Proteins/metabolism*; Chromatin/metabolism*; Chromosomal Proteins, Non-Histone/metabolism*; Computer Simulation; DNA/metabolism*; Female; Gene Expression*; Liver/metabolism*; Male; Mice; Protein Binding