1. Chromosomes and Gene Expression
  2. Computational and Systems Biology
Download icon

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
Research Article
  • Cited 0
  • Views 574
  • Annotations
Cite as: eLife 2018;7:e34077 doi: 10.7554/eLife.34077

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.

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 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 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, Reviewing Editor

Publication history

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

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.

Metrics

  • 574
    Page views
  • 153
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology and Stem Cells
    Jan J Zylicz et al.
    Research Advance Updated
    1. Cell Biology
    2. Chromosomes and Gene Expression
    Madhav Jagannathan et al.
    Research Article Updated