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Topologically associated domains: a successful scaffold for the evolution of gene regulation in animals

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The evolution of gene regulation is considered one of the main drivers causing the astonishing morphological diversity in the animal kingdom. Gene regulation in animals heavily depends upon cis‐regulatory elements, discrete pieces of DNA that interact with target promoters to regulate gene expression. In the last years, Chromosome Conformation Capture experiments (4C‐seq, 5C, and HiC) in several organisms have shown that the genomes of many bilaterian animals are organized in the 3D chromatin space in compartments called topologically associated domains (TADs). The appearance of the architectural protein CTCF in the bilaterian ancestor likely facilitated the origin of this chromatin 3D organization. TADs play a critical role favoring the contact of cis‐regulatory elements with their proper target promoters (that often lay within the same TAD) and preventing undesired regulatory interactions with promoters located in neighboring TADs. We propose that TAD may have had a major influence in the history of the evolution of gene regulation. They have contributed to the increment of regulatory complexity in bilaterians by allowing newly evolved cis‐regulatory elements to find target promoters in a range of hundreds of kilobases. In addition, they have conditioned the mechanisms of evolution of gene regulation. These mechanisms include the appearance, removal, or relocation of TAD borders. Such architectural changes have been able to wire or unwire promoters with different sets of cis‐regulatory elements in a single mutational event. We discuss the contribution of these architectural changes to the generation of critical genomic 3D structures required for new regulatory mechanisms associated to morphological novelties. WIREs Dev Biol 2017, 6:e265. doi: 10.1002/wdev.265 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Comparative Development and Evolution > Evolutionary Novelties
The elaboration of the bipartite regulation of the HoxD cluster in vertebrates required several modifications of topologically associated domains (TAD) architectures between the last common ancestor of chordates and the last common ancestor of vertebrates. In vertebrates, the regulatory information governing HoxD genes expression is distributed in two adjacent TADs (see HiC heatmap for the mouse cluster at the bottom right square). HoxD genes are located precisely over the TAD boundary separating these two adjacent TADs. Genes located at the 3 end of the cluster contact preferentially cis‐regulatory elements (CREs) from the 3 TAD (in blue). Genes at the 5 end of the cluster preferentially interact with CREs from the 5 TAD (red). In the cephalochordate amphioxus, all Hox genes are embedded within the same TAD. This TAD also includes the neighboring 3 genomic region, which shows conserved synteny with vertebrates (top right square). On the left, a hypothetical evolutionary scenario showing the changes in Hox clusters topologies that may have occurred after the divergence of vertebrates and amphioxus from their chordate ancestor. The scenario includes a genomic rearrangement that brought the vertebrate‐specific 5 TAD region to the proximity of the cluster and the partitioning of the Hox regulatory landscape into two adjacent TADs. Additional events include the formation of gene deserts in the HoxD cluster after the whole genome duplications in vertebrates and a tandem duplication of the Evx gene in the amphioxus lineage.
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Genes can be exposed to new regulatory information in an unproductive and a productive manner. (a) The appearance of a new cis‐regulatory element (CRE) whose regulatory information is incompatible with that already present in the topologically associated domains (TAD). A new CRE (blue oval in the red TAD pointed by a black arrowhead) promotes expression in a different cell population than the rest of CREs in this TAD. In this cell population, the TAD (colored in red) is in a closed B compartment associated to the nuclear lamina, which prevents the activation of the new CRE. (b) Modification of a TAD structure by a genomic rearrangement (in this case an inversion). This rearrangement relocates a gene into a new regulatory environment active in a different cell population. In this example, a gene that is not expressed in limbs, after an inversion, integrates in a different TAD with a set of limb CREs that activates it in this territory. This may in turn cause morphological changes, as reported recently.
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Examples of possible changes in gene expression that could putatively arise by the incorporation of new regulatory DNA without dismantling the architecture of a pre‐existing topologically associated domain (TAD). (a) TADs are flexible to changes in size, as observed when comparing chromosome conformation capture data from orthologous syntenic regions in two different organisms, such as the Irx3 and the irx3a loci of mouse and zebrafish respectively. HiC heatmap of the mouse Irx3 genomic region (at the top) was obtained from public HiC matrices. The 4C‐seq profiles of mouse Irx3 (top) and zebrafish irx3a (bottom) loci are from published data. Below, a simplified cartoon of the putative HiC heatmap around the zebrafish irx3a locus based on 4C‐seq data is shown. Interestingly, 4C‐seq profiles from both species are largely similar and contact limits are placed in equivalent conserved syntenic regions (near the Chd9/chd9 and Lpcat2/lpcat2 genes). Limits are compatible with the TAD border prediction in mouse (black triangle in mouse HiC heatmap). However, the Irx3 regulatory landscape in mouse is 600 kb bigger than the one of irx3a in zebrafish. In (b) there is a simplified model of the two TADs sharing the overall architecture and the syntenic location of the boundaries, but differing in size and in part of the regulatory content.
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Benefits of including C‐techniques data in comparative genomics projects. (a) cis‐Regulatory element (CRE)–promoter assignment based on contacts is much more reliable than association by proximity, especially for developmental genes with extended regulatory landscapes. Filtering out promoters that are likely insensitive to long‐range regulation (colored in gray in the figure) may help to refine further this assignment process. (b) Chromatin structural information complements epigenomic data used to identify CRE elements. Among the different epigenomic data, chromatin accessibility based techniques (DNAse‐seq, ATAC‐seq), are able to reach base‐pair resolution and reveal transcription factor footprinting. In the simplified diagram, the comparison of the CRE transcription factor binding site composition of two orthologous topologically associated domains (TADs) permits to unveil the genetic determinants that allow the gene A to gain a new expression domain in muscle.
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Evidence supporting that topologically associated domains (TADs) are a widespread feature of bilaterian genomes. (a) Phylogenetic tree showing current TAD evidence in several representative animal species (branches are not to scale). Animal cartoons are colored in blue when there is strong evidence of TAD chromatin organization, red when the absence of TADs has been experimentally demonstrated and black when there is not enough data to support either scenario. HiC heatmaps of Hox genes regions are also shown when available. Heatmaps were plotted from public HiC matrices of the mouse HoxD cluster, the Drosophila Antennapedia cluster and the region within the lin‐39 and the egl‐5 homeobox genes in Caenorhabditis elegans. For zebrafish HoxDa and amphioxus Hox clusters, virtual HiC heatmaps are shown. Numbers of conserved syntenic pairs were obtained from Irimia et al. (b) Evidence of TADs in sea urchin arises from the study of the Six locus architecture. A conserved topological boundary is placed bisecting Six gene clusters into two regulatory landscapes, both in zebrafish and sea urchin. This is revealed by similar 4C‐seq profiles in both organisms. This shared chromatin configuration results in markedly different expression patterns of genes located on each side of the boundary, which are controlled by two different sets of cis‐regulatory elements (CREs). The same syntax of diverging CTCF binding sites (black arrowheads) operates in both species in order to generate TAD boundaries.
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