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Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding

  1. Stefan Mundlos1,3,5
  1. 1RG Development & Disease, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany;
  2. 2Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany;
  3. 3Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany;
  4. 4Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany;
  5. 5Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
  1. Corresponding author: mundlos{at}molgen.mpg.de
  1. 6 These authors contributed equally to this work.

Abstract

Complex regulatory landscapes control the pleiotropic transcriptional activities of developmental genes. For most genes, the number, location, and dynamics of their associated regulatory elements are unknown. In this work, we characterized the three-dimensional chromatin microarchitecture and regulatory landscape of 446 limb-associated gene loci in mouse using Capture-C, ChIP-seq, and RNA-seq in forelimb, hindlimb at three developmental stages, and midbrain. The fine mapping of chromatin interactions revealed a strong preference for functional genomic regions such as repressed or active domains. By combining chromatin marks and interaction peaks, we annotated more than 1000 putative limb enhancers and their associated genes. Moreover, the analysis of chromatin interactions revealed two regimes of chromatin folding, one producing interactions stable across tissues and stages and another one associated with tissue and/or stage-specific interactions. Whereas stable interactions associate strongly with CTCF/RAD21 binding, the intensity of variable interactions correlates with changes in underlying chromatin modifications, specifically at the viewpoint and at the interaction site. In conclusion, this comprehensive data set provides a resource for the characterization of hundreds of limb-associated regulatory landscapes and a framework to interpret the chromatin folding dynamics observed during embryogenesis.

Footnotes

  • Received July 22, 2016.
  • Accepted December 6, 2016.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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