Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver

  1. Bryan J Matthews
  2. David J Waxman  Is a corresponding author
  1. Boston University, United States

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.

Data availability

Data generated and used in this study has been deposited in the Gene Expression Omnibus (GEO) under accession number GSE102999 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102999). ChIP-seq data are available under the subseries GSE102997 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102997). 4C-seq data are available under the subseries GSE102998 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102998). Published datasets used in this study are listed in Table S4.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Bryan J Matthews

    Department of Biology, Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1930-339X
  2. David J Waxman

    Department of Biology, Boston University, Boston, United States
    For correspondence
    djw@bu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7982-9206

Funding

National Institutes of Health (DK33765)

  • David J Waxman

National Science Foundation (DGE-1247312)

  • Bryan J Matthews

National Institutes of Health (ES024421)

  • David J Waxman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Adult male and female CD-1 mice (ICR strain) were purchased from Charles River Laboratories (Wilmington, MA) and were housed in the Boston University Laboratory Animal Care Facility. Animals were treated using protocols specifically reviewed for ethics and approved by Boston University's Institutional Animal Care and Use Committee (IACUC; protocol 16-003).

Reviewing Editor

  1. Noam Kaplan

Publication history

  1. Received: December 6, 2017
  2. Accepted: April 30, 2018
  3. Accepted Manuscript published: May 14, 2018 (version 1)
  4. Version of Record published: June 4, 2018 (version 2)

Copyright

© 2018, Matthews & Waxman

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Bryan J Matthews
  2. David J Waxman
(2018)
Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver
eLife 7:e34077.
https://doi.org/10.7554/eLife.34077

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