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

Ana Rita Amândio,Lucille Lopez-Delisle,Bénédicte Mascrez,Christopher Chase Bolt,Denis Duboule

doi:10.7554/elife.52962

Ana Rita Amândio, Lucille Lopez-Delisle + Show 3 more

Open Access

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

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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.

Highlights

During mammalian development, the organization of body structures and their morphogenesis require the accurate transcriptional regulation of the Hox gene family of transcription factors
Studies of the HoxD cluster have provided some insights into this question (Lonfat et al, 2014) and suggested that the regulation of Hoxd13 is primarily achieved by the C-DOM topologically-associating domains (TADs), a large regulatory landscape flanking the gene cluster on its centromeric side, which controls Hoxd gene activation in the developing digits
The chromatin interaction profile displayed some differences in transcriptionally active cells, even though the global TAD structure remained unchanged, suggesting that a C-DOM internal chromatin micro-organization had occurred due to the implementation of various digit-specific enhancers

Summary

Introduction

The organization of body structures and their morphogenesis require the accurate transcriptional regulation of the Hox gene family of transcription factors These proteins instruct progenitor cells at different levels along the main anterior to posterior axis, about their developmental fates. Genetic and biochemical analyses have shown that this entire regulatory landscape is shared between GT and digits, and contains multiple enhancer sequences that are active in either both or only one of these developing structures (Gonzalez et al, 2007; Lonfat et al, 2014; Montavon et al, 2011)

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