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Conservation and divergence of regulatory strategies and the origin of tetrapod digits

ABSTRACT: The evolution of tetrapod limbs from fish fins enabled the conquest of land by vertebrates and thus represents a key step in evolution. Despite the use of comparative gene expression analyses, critical aspects of this transformation remain controversial, in particularly the origin of digits. Hoxa and Hoxd genes are essential for the specification of the different limb segments and their functional abrogation leads to large truncations of the appendages. Here we show that the selective transcription of mouse Hoxa genes in proximal and distal limbs is related to a bimodal higher order chromatin structure, similar to that reported for Hoxd genes, thus revealing a generic regulatory strategy implemented by both gene clusters during limb development. We found the same bimodal chromatin architecture in fish embryos, indicating that the regulatory strategy used to pattern tetrapod limbs predates the divergence between fish and tetrapods. However, when assessed in mice, both fish regulatory domains triggered transcription in proximal, rather than distal limb territories, supporting an evolutionary scenario whereby digits arose as true tetrapod novelties through genetic retrofitting of a preexisting bimodal chromatin framework. We discuss the possibility to consider regulatory circuitries, rather than expression patterns, as essential parameters to define evolutionary synapomorphies. Circular Chromosome Conformation Capture (4C seq) at the mouse HoxA and HoxD loci in proximal and distal forelimbs and forebrain at E12.5 and at the zebrafish HoxAa, HoxAb and HoxDa loci in 5 dpf whole embryos.

ORGANISM(S): Mus musculus

SUBMITTER: Marion LELEU

PROVIDER: E-GEOD-47644 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Conservation and divergence of regulatory strategies and the origin of tetrapod digits

Project description:The evolution of tetrapod limbs from fish fins enabled the conquest of land by vertebrates and thus represents a key step in evolution. Despite the use of comparative gene expression analyses, critical aspects of this transformation remain controversial, in particularly the origin of digits. Hoxa and Hoxd genes are essential for the specification of the different limb segments and their functional abrogation leads to large truncations of the appendages. Here we show that the selective transcription of mouse Hoxa genes in proximal and distal limbs is related to a bimodal higher order chromatin structure, similar to that reported for Hoxd genes, thus revealing a generic regulatory strategy implemented by both gene clusters during limb development. We found the same bimodal chromatin architecture in fish embryos, indicating that the regulatory strategy used to pattern tetrapod limbs predates the divergence between fish and tetrapods. However, when assessed in mice, both fish regulatory domains triggered transcription in proximal, rather than distal limb territories, supporting an evolutionary scenario whereby digits arose as true tetrapod novelties through genetic retrofitting of a preexisting bimodal chromatin framework. We discuss the possibility to consider regulatory circuitries, rather than expression patterns, as essential parameters to define evolutionary synapomorphies.

2014-01-21 | GSE47644 | GEO

Transcription landscape at the HoxD locus in developing limbs and brain

Project description:The emergence and evolution of digits was an essential step in the success of the tetrapod lineage. Amongst the key players, Hoxd genes were functionally co-opted in the developing digital plate, where they help organize growth and patterns. To understand both the evolutionary recruitment and transcriptional regulation of this genomic locus, we analyzed its architecture and chromatin status in developing digits, combined with a deletion approach in vivo. We show that the active and inactive parts of the gene cluster adopt opposite spatial configurations, corresponding to different chromatin domains. Active genes are contacted by several regulatory islands, located within a neighboring gene desert, which contribute quantitatively or qualitatively to the global transcriptional readout. We refer to this novel type of control as a ‘regulatory archipelago’ and discuss the value of this concept to understand both the morphological flexibility of tetrapod digits and the robustness of the underlying developmental process. Transcriptional activity at the Hoxd locus in developing limbs and brain at E12.5

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Project description:The emergence and evolution of digits was an essential step in the success of the tetrapod lineage. Amongst the key players, Hoxd genes were functionally co-opted in the developing digital plate, where they help organize growth and patterns. To understand both the evolutionary recruitment and transcriptional regulation of this genomic locus, we analyzed its architecture and chromatin status in developing digits, combined with a deletion approach in vivo. We show that the active and inactive parts of the gene cluster adopt opposite spatial configurations, corresponding to different chromatin domains. Active genes are contacted by several regulatory islands, located within a neighboring gene desert, which contribute quantitatively or qualitatively to the global transcriptional readout. We refer to this novel type of control as a ‘regulatory archipelago’ and discuss the value of this concept to understand both the morphological flexibility of tetrapod digits and the robustness of the underlying developmental process. Chromosome Conformation Capture-on-chip analysis (4C) at the Hoxd locus in developing limbs and brain at E12.5

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Chromatin landscape at the HoxD locus in developing digits and forebrain

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2013-06-07 | E-GEOD-45455 | biostudies-arrayexpress

A Switch Between Topological Domains Underlies HoxD Genes Collinearity in Mouse Limbs (ChIP-Seq)

Project description:During limb development, Hoxd genes are transcribed in two waves: Early on, when the arm and forearm are specified and subsequently, when digits form. While the latter phase is controlled by enhancers centromeric to the HoxD cluster, we show here that the early phase requires enhancers located in the opposite telomeric gene desert. The transition between the two types of regulations involves a functional switch between two distinct topological domains, as reflected by a subset of genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently shift to establish new contacts on the opposite side. This transition between two regulatory landscapes generates an intermediate area of low Hox dose developing into the wrist, the transition between our arms and our hands. This intriguing correspondence between genomic and morphological boundaries illustrates the mechanism underlying collinear Hox gene regulation in our developing appendages. Chromatin ImmunoPrecipitation and Sequencing (ChIP-seq) of H3K27A in developing proximal and distal limbs at E9.5, E10.5 and E12.5

2013-06-07 | E-GEOD-45456 | biostudies-arrayexpress

Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs

Project description:HoxA genes exhibit central roles during development and causal mutations have been found in several human syndromes including limb malformation. Despite their importance, information on how these genes are regulated is lacking. Here, we report on the first identification of bona fide transcriptional enhancers controlling HoxA genes in developing limbs and show that these enhancers are grouped into distinct topological domains at the sub-megabase scale (sub-TADs). We provide evidence that target genes and regulatory elements physically interact with each other through contacts between sub-TADs rather than by the formation of discreet "DNA loops". Interestingly, there is no obvious relationship between the functional domains of the enhancers within the limb and how they are partitioned among the topological domains, suggesting that sub-TAD formation does not rely on enhancer activity. Moreover, we show that suppressing the transcriptional activity of enhancers does not abrogate their contacts with HoxA genes. Based on these data, we propose a model whereby chromatin architecture defines the functional landscapes of enhancers. From an evolutionary standpoint, our data points to the convergent evolution of HoxA and HoxD regulation in the fin-to-limb transition, one of the major morphological innovations in Vertebrates. The chromatin binding of the RNA polymerase II and the sub-unit Med12 of the Mediator complexe were analysed by ChIP-sequencing mouse distal E11.5 forelimb. This approach allowed us to identify the position of limb-specific enhancers.

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Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs

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Reorganization of HoxD regulatory landscapes during the evolution of a snake-like body plan (ChIP-seq)

Project description:While the vertebrate body plan is highly conserved amongst all species of this taxon, extreme variations thereof can be documented in snakes, which display both an absence of limbs and an unusually elongated trunk. As Hox genes are strong candidates both for the making and the evolution of this body plan, their comparative study in such a morphologically diverged group is informative regarding their potential causative importance in these processes. In this work we use an interspecies comparative approach where different aspects of regulation at the HoxD locus are investigated. We find that although spatial collinearity and associated epigenetic mark dynamics are conserved in the corn snake, other regulatory modalities have been largely restructured. A BAC transgenic approach indeed revealed that, while the majority of mesodermal enhancers in vertebrates appear to be mostly located outside of the cluster, the corn snake contains most mesodermal trunk enhancers within the HoxD cluster. We also find that, despite the absence of limbs and an altered Hoxd gene regulation in external genitalia, the bimodal chromatin structure at the corn snake HoxD locus is maintained. The analysis of particular enhancer sequences initially defined in the mouse and further isolated at the snake orthologous locus showed differences in their specificities for the limb and genital bud expression. Of particular interest, a snake counterpart of a mouse limb-only enhancer sequence evolved into a genital-only enhancer. Such a regulatory exaptation suggests that enhancer versatility may have been an important factor to accompany the transition towards the snake body plan. These results show that vertebrate morphological evolution is likely to have been associated with extensive reorganization at the HoxD regulatory landscapes while respecting a very conserved general regulatory framework.

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Reorganization of HoxD regulatory landscapes during the evolution of a snake-like body plan (4C-seq)

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