A complex regulatory landscape involved in the development of mammalian external genitals

  1. Ana Rita Amândio
  2. Lucille Lopez-Delisle
  3. Christopher Chase Bolt
  4. Bénédicte Mascrez
  5. Denis Duboule  Is a corresponding author
  1. Ecole Polytechnique Fédérale de Lausanne, Switzerland
  2. University of Geneva, Switzerland

Abstract

Developmental genes are often controlled by large regulatory landscapes matching topologically associating domains (TADs). In various contexts, the associated chromatin backbone is modified by specific enhancer-enhancer and enhancer-promoter interactions. We used a TAD flanking the mouse HoxD cluster to study how these regulatory architectures are formed and deconstructed once their function achieved. We describe this TAD as a functional unit, with several regulatory sequences acting together to elicit a transcriptional response. With one exception, deletion of these sequences didn't modify the transcriptional outcome, a result at odds with a conventional view of enhancer function. The deletion and inversion of a CTCF site located near these regulatory sequences did not affect transcription of the target gene. Slight modifications were nevertheless observed, in agreement with the loop extrusion model. We discuss these unexpected results considering both conventional and alternative explanations relying on the accumulation of poorly specific factors within the TAD backbone.

Data availability

All raw and processed RNA-seq, 4C-seq, ChIP-seq, Cut & Run, and ATAC-seq datasets are available in the Gene Expression Omnibus (GEO) repository under accession number GSE138514

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

Article and author information

Author details

  1. Ana Rita Amândio

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0634-4042
  2. Lucille Lopez-Delisle

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Christopher Chase Bolt

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3544-3552
  4. Bénédicte Mascrez

    University of Geneva, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Denis Duboule

    School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    For correspondence
    denis.duboule@epfl.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9961-2960

Funding

Swiss National Science Foundation (310030B_138662)

  • Denis Duboule

European Research Council (588029)

  • Denis Duboule

National Institutes of Health (NICHD F32HD0935)

  • Christopher Chase Bolt

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

Reviewing Editor

  1. Job Dekker, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: All experiments were performed in agreement with the Swiss law on animal protection (LPA), under license No GE 81/14 (to DD).

Version history

  1. Received: October 22, 2019
  2. Accepted: April 17, 2020
  3. Accepted Manuscript published: April 17, 2020 (version 1)
  4. Version of Record published: April 27, 2020 (version 2)

Copyright

© 2020, Amândio et al.

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. Ana Rita Amândio
  2. Lucille Lopez-Delisle
  3. Christopher Chase Bolt
  4. Bénédicte Mascrez
  5. Denis Duboule
(2020)
A complex regulatory landscape involved in the development of mammalian external genitals
eLife 9:e52962.
https://doi.org/10.7554/eLife.52962

Share this article

https://doi.org/10.7554/eLife.52962

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