Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci

Darbellay, Fabrice; Duboule, Denis

doi:10.1016/bs.ctdb.2015.11.022

Cited by 38 publications

(43 citation statements)

References 58 publications

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“…The boundaries that define which Hox genes are expressed or repressed correlate with CTCF binding sites in Drosophila and are disrupted by mutation of CTCF binding sites in mammals (Bowman et al, 2014; Narendra et al, 2015). These boundaries are proposed to define domains of long-range interaction that tie distant enhancer regions to Hox genes, within specific TAD domains, and thereby determine the activation of these genes in a spatially appropriate manner (Andrey et al, 2013; Darbellay and Duboule, 2016; Noordermeer et al, 2011). If PRC1 generates separate compacted domains that drive repression of its target genes, these domains would likely be smaller than megabase TAD domains.…”

Section: Introductionmentioning

confidence: 99%

Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation

et al. 2017

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Summary Master regulatory genes require stable silencing by the Polycomb-Group (PcG) to prevent misexpression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in ES cells and neural progenitors using 5C and super-resolution microscopy. The genomic loci of repressed PcG targets formed discrete, small (20-140Kb) domains of tight interaction that corresponded to locations bound by canonical Polycomb Repressive Complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1, and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in size and boundary characteristics. These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher order structure.

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Section: Introductionmentioning

confidence: 99%

Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation

et al. 2017

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“…Although this clustered organization facilitates their coordinated transcriptional activation during the elongation of the major body axis (10,15), it also favors the evolution of global regulations outside the gene clusters themselves (16). Consequently, specific subgroups of Hox genes, at least within the HoxA and HoxD clusters, are controlled by the same series of global enhancers; hence, they are coregulated in different contexts, which provide the system with both quantitative and qualitative modulations.…”

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confidence: 99%

“…Within the T-DOM, series of enhancers are found, which regulate groups of genes lying in the central part of the cluster, as if the regulatory sequences would contact a chromatin pocket encompassing Hoxd8 to Hoxd11 (18). These large and apparently constitutive chromosome domains (TADs) may facilitate the required regulatory switches at important developmental loci, and were also proposed to have triggered the evolution of pleiotropy by providing the regulatory context for evolving novel enhancers (16,19).…”

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confidence: 99%

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Schep

Necşulea

Rodríguez-Carballo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Vertebrate Hox genes encode transcription factors operating during the development of multiple organs and structures. However, the evolutionary mechanism underlying this remarkable pleiotropy remains to be fully understood. Here, we show that Hoxd8 and Hoxd9, two genes of the HoxD complex, are transcribed during mammary bud (MB) development. However, unlike in other developmental contexts, their coexpression does not rely on the same regulatory mechanism. Hoxd8 is regulated by the combined activity of closely located sequences and the most distant telomeric gene desert. On the other hand, Hoxd9 is controlled by an enhancer-rich region that is also located within the telomeric gene desert but has no impact on Hoxd8 transcription, thus constituting an exception to the global regulatory logic systematically observed at this locus. The latter DNA region is also involved in Hoxd gene regulation in other contexts and strongly interacts with Hoxd9 in all tissues analyzed thus far, indicating that its regulatory activity was already operational before the appearance of mammary glands. Within this DNA region and neighboring a strong limb enhancer, we identified a short sequence conserved in therian mammals and capable of enhancer activity in the MBs. We propose that Hoxd gene regulation in embryonic MBs evolved by hijacking a preexisting regulatory landscape that was already at work before the emergence of mammals in structures such as the limbs or the intestinal tract.enhancers | TAD | mammalian development | mammary gland

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“…Vertebrate Hox gene clusters display both a gene density and a level of organization thus far unmatched across metazoans, suggesting that a consolidation process occurred along with the evolution of the vertebrate lineage. This counterintuitive conclusion (Duboule 2007) was tentatively explained by the emergence and implementation of global and long-range regulatory controls (Darbellay and Duboule 2016), which was itself made possible by the two rounds of genome amplification that occurred at the root of vertebrates (Ohno 1970;Holland et al 1994). In this view, Hox genes became progressively more tightly organized to better respond to these remote regulations, a process that allowed the emergence of a coordinated regulation and lead to functional complexity and redundancy.…”

Section: Discussionmentioning

confidence: 99%

“…In this view, the duplication of genomic Hox loci may have allowed the emergence of multiple potent enhancer sequences located outside the clusters and controlling several Hox genes at once. The potential negative effects of such high-order regulations and structures, for example upon the ancestral colinear mechanism at work during axial extension, could have been compensated for by having several clusters implementing this colinear process at the same time (Darbellay and Duboule 2016).…”

Section: Introductionmentioning

confidence: 99%

Constrained Transcriptional Polarity in the Organization of MammalianHoxGene Clusters

Darbellay

Bochaton

Lopez-Delisle

et al. 2019

Preprint

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In many animal species with a bilateral symmetry, Hox genes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrate Hox clusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters towards a tighter structure during the evolution of the vertebrate lineage. Here we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster such as to invert one or several transcription unit(s), with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hox clusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in cis.

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Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci

Cited by 38 publications

References 58 publications

Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation

Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

Constrained Transcriptional Polarity in the Organization of MammalianHoxGene Clusters

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