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.
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).
Reviewing Editor
- Job Dekker, University of Massachusetts Medical School, United States
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
Further reading
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Gene expression has been employed for homologizing body regions across bilateria. The molecular comparison of vertebrate and fly brains has led to a number of disputed homology hypotheses. Data from the fly Drosophila melanogaster have recently been complemented by extensive data from the red flour beetle Tribolium castaneum with its more insect-typical development. In this review, we revisit the molecular mapping of the neuroectoderm of insects and vertebrates to reconsider homology hypotheses. We claim that the protocerebrum is non-segmental and homologous to the vertebrate fore- and midbrain. The boundary between antennal and ocular regions correspond to the vertebrate mid-hindbrain boundary while the deutocerebrum represents the anterior-most ganglion with serial homology to the trunk. The insect head placode is shares common embryonic origin with the vertebrate adenohypophyseal placode. Intriguingly, vertebrate eyes develop from a different region compared to the insect compound eyes calling organ homology into question. Finally, we suggest a molecular re-definition of the classic concepts of archi- and prosocerebrum.
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The attachment site of the rotator cuff (RC) is a classic fibrocartilaginous enthesis, which is the junction between bone and tendon with typical characteristics of a fibrocartilage transition zone. Enthesis development has historically been studied with lineage tracing of individual genes selected a priori, which does not allow for the determination of single-cell landscapes yielding mature cell types and tissues. Here, in together with open-source GSE182997 datasets (three samples) provided by Fang et al., we applied Single-cell RNA sequencing (scRNA-seq) to delineate the comprehensive postnatal RC enthesis growth and the temporal atlas from as early as postnatal day 1 up to postnatal week 8. And, we furtherly performed single-cell spatial transcriptomic sequencing on postnatal day 1 mouse enthesis, in order to deconvolute bone-tendon junction (BTJ) chondrocytes onto spatial spots. In summary, we deciphered the cellular heterogeneity and the molecular dynamics during fibrocartilage differentiation. Combined with current spatial transcriptomic data, our results provide a transcriptional resource that will support future investigations of enthesis development at the mechanistic level and may shed light on the strategies for enhanced RC healing outcomes.
