Chromatin organization and global regulation of Hox gene clusters

Denis Duboule
Royal Soc, 2013
Article

During development, a properly coordinated expression of Hox genes, within their different genomic clusters is critical for patterning the body plans of many animals with a bilateral symmetry. The fascinating correspondence between the topological organization of Hox clusters and their transcriptional activation in space and time has served as a paradigm for understanding the relationships between genome structure and function. Here, we review some recent observations, which revealed highly dynamic changes in the structure of chromatin at Hox clusters, in parallel with their activation during embryonic development. We discuss the relevance of these findings for our understanding of large-scale gene regulation.

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Denis Duboule
Royal Soc, 2013
Article

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https://infoscience.epfl.ch/record/186573?ln=fr

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Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci

Denis Duboule, Marion Leleu, Daniël Noordermeer, Patrick Schorderet

Hox genes are essential regulators of embryonic development. Their step-wise transcriptional activation follows their genomic topology and the various states of activation are subsequently memorized into domains of progressively overlapping gene products. We have analyzed the 3D chromatin organization of Hox clusters during their early activation in vivo, using high-resolution circular chromosome conformation capture. Initially, Hox clusters are organized as single chromatin compartments containing all genes and bivalent chromatin marks. Transcriptional activation is associated with a dynamic bi-modal 3D organization, whereby the genes switch autonomously from an inactive to an active compartment. These local 3D dynamics occur within a framework of constitutive interactions within the surrounding Topological Associated Domains, indicating that this regulation process is mostly cluster intrinsic. The step-wise progression in time is fixed at various body levels and thus can account for the chromatin architectures previously described at a later stage for different anterior to posterior levels.DOI: http://dx.doi.org/10.7554/eLife.02557.001.

Elife Sciences Publications Ltd2014

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The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development

Denis Duboule

This study reports the structure of the mouse homeobox-containing gene Hox-1.4 of the HOX-1 cluster, as well as its expression pattern during embryonic and fetal development. The overall structure of this gene includes two major exons, the second of which encodes the homeo-domain. The putative Hox-1.4 protein displays similarities with products of homologous genes located at the same relative positions in other HOX clusters. A fragment extending 360 base pairs (bp) upstream of a transcriptional start site was shown to be able to promote transcription in transfected cells. This fragment is GC-rich and contains binding sites for the Sp1 transcription factor. In situ hybridization studies revealed the Hox-1.4 expression pattern during development. As already reported for several other murine Hox genes, Hox-1.4 is expressed in the fetal central nervous system (CNS), in structures derived from somitic mesodermal condensations (sclerotomes, prevertebrae) as well as in several mesodermal components of various organs and structures such as lungs, gut, stomach, intestine and meso- and metanephros. This expression pattern is in good agreement with recent proposals concerning the involvement of such genes in the establishment of the vertebrate body plan as well as the relationship between the positions of these genes within their clusters and the anteroposterior restriction of their expression domains.

1989

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An ancestral regulatory mechanism underlies Hoxd gene expression in both developing genitals and digits

Nicolas Lonfat

Coordinated expression of HoxD cluster genes is crucial for the emergence and patterning of both developing digits and external genitalia. As a shared evolutionary origin has been proposed for these secondary structures, which may have accompanied the transition from an aquatic towards a terrestrial life, we investigated whether the regulatory circuitries would also share similarities, indicating a common phylogenetic origin. We show that the transcription of posterior Hoxd genes in the distal part of these different appendages depends, in both cases, upon enhancer sequences located centromeric to the cluster, in a gene poor region, previously described as forming a regulatory archipelago in digit cells. Analysis of the epigenetic status and spatial conformation of the HoxD cluster and its centromeric neighborhood has identified several putative regulatory elements that interact with Hoxd genes via chromatin looping in the developing genital tubercle. In vivo, targeted deletions within the centromeric gene desert further revealed the requirement of these sequences for Hoxd genes transcription in this embryonic structure. We used lentivirus-mediated transgenesis to evaluate the enhancer activity of the identified regulatory elements. While some sequences were able to drive a reporter gene in both digits and genitalia, others were specific for either one of these two structures. We identified Cdx2 transcription factor as a putative interactor of the genitalspecific enhancers. These results suggest a common ancestral regulatory strategy for digits and genitals, yet with specific adaptations in each developmental context. This work should help understand the regulatory mechanism underlying Hoxd gene expression in the genital tubercle and digits, as well as the phylogenetic histories of such global regulations.

EPFL2013

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Gène Hox

Les gènes Hox sont une catégorie particulière de gènes homéotiques ; ils sont parmi les gènes les plus longuement étudiés de la biologie évolutive. Les gènes homéotiques possèdent une séquence ADN qua

Expression génétique

L'expression des gènes, encore appelée expression génique ou expression génétique, désigne l'ensemble des processus biochimiques par lesquels l'information héréditaire stockée dans un gène est lue po

Chromatine

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