A complex regulatory landscape involved in the development of mammalian external genitals
- Ecole Polytechnique Fédérale de Lausanne, Switzerland
- 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
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A complex regulatory landscape involved in the development of external genitalsNCBI Gene Expression Omnibus, GSE138514.
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Transcriptomic analysis of wild type and Del(Hotair)-/- mouse tissuesNCBI Gene Expression Omnibus, GSE79028.
Article and author information
Author details
Christopher Chase Bolt
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
- 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
- Received: October 22, 2019
- Accepted: April 17, 2020
- Accepted Manuscript published: April 17, 2020 (version 1)
- 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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A complex regulatory landscape involved in the development of mammalian external genitals
eLife 9:e52962.
https://doi.org/10.7554/eLife.52962
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