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.
Highlights
The mammalian genome is organized into stereotypical domains, averaging ~700 kb in length, called Topologically Associating Domains (TADs) (Dixon et al, 2012; Nora et al, 2012)
We characterized TADs identified in mouse liver (Vietri Rudan et al, 2015) using matched Chromatin immunoprecipitation (ChIP)-seq datasets for CTCF and the cohesin subunit Rad21, which we obtained for a group of individual adult male mouse livers
We explored the impact of cohesin depletion on CAC sites associated with TAD boundaries, following up on the finding that many cohesin binding sites are maintained upon knockout or knockdown of components of the cohesin complex (Faure et al, 2012)
Summary
The mammalian genome is organized into stereotypical domains, averaging ~700 kb in length, called Topologically Associating Domains (TADs) (Dixon et al, 2012; Nora et al, 2012). TADs are insulated chromatin domains whose genomic boundaries are often retained across tissues (Dixon et al, 2012) and have been conserved during mammalian evolution (Vietri Rudan et al, 2015; Dixon et al, 2015). TADs show substantial overlap with features of nuclear organization identified using other approaches, including replication domains, lamina-associated domains, and A/B chromatin compartments (Dixon et al, 2015; Pope et al, 2014; Nora et al, 2013). While TAD structures are often shared across tissues within a species, some individual TADs show tissue-specific differences in their spatial positioning within the nucleus, and in their overall activity, transcription factor (TF) binding patterns, and patterns of expression of individual genes
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