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WIREs Dev Biol
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Gene regulation during development in the light of topologically associating domains

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During embryonic development, complex transcriptional programs govern the precision of gene expression. Many key developmental genes are regulated via cis‐regulatory elements that are located far away in the linear genome. How sequences located hundreds of kilobases away from a promoter can influence its activity has been the subject of numerous speculations, which all underline the importance of the 3D‐organization of the genome. The recent advent of chromosome conformation capture techniques has put into focus the subdivision of the genome into topologically associating domains (TADs). TADs may influence regulatory activities on multiple levels. The relative invariance of TAD limits across cell types suggests that they may form fixed structural domains that could facilitate and/or confine long‐range regulatory interactions. However, most recent studies suggest that interactions within TADs are more variable and dynamic than initially described. Hence, different models are emerging regarding how TADs shape the complex 3D conformations, and thereafter influence the networks of cis‐interactions that govern gene expression during development. WIREs Dev Biol 2016, 5:169–185. doi: 10.1002/wdev.218 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms
Regulatory genome architecture: Topologically associating domains (TADs), Regulatory domains (RDs) and gene‐enhancers. (a) Representation of a hypothetical locus. HiC interaction frequencies are displayed as a two‐dimensional heatmap, where intra‐TAD contacts are more frequent than inter‐TAD contacts. TADs and RDs are represented as bars; genes and enhancers are depicted as arrows and ovals, respectively. From Hi‐C heatmaps, one can envision TADs as entangled skeins of DNA (bottom). (b) TADs confine cis‐regulatory elements and target gene promoters in space and may constrain the diffusion of factors required for transcriptional activity. This facilitates regulatory interactions and at the same time prevents unwanted regulatory activity across TADs transitions, as in (c) where a putative deletion of a transition causes ectopic expression of a gene in an adjacent TAD. TAD transition is shadowed in grey and transcription factors are depicted as small hexagons.
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(a) HoxD expression in the limb bud (right) is achieved by gathering regulatory islands and gene promoters in space (left). (Ref ) (b) Inter‐chromosomal ‘regulatory archipelago’ controls the single allelic expression of olfactory receptor genes. (c) Representation of a broadly invariant domain within which different dynamic regulatory interactions can potentially occur. Enhancers and genes are represented with ovals and arrows, respectively.
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Understanding the mouse Pax1Un‐s mutant in the light of TAD organization. Pax1 and Nkx2‐2 expression in wild type and undulated mutant allele is shown. Ectopic expression of Nkx2‐2 is only detected in a large deletion (Pax1Un‐s) (Ref ) presumably fusing two adjacent TADs harboring Nkx2‐2 and Pax1, respectively. This would allow Pax1 enhancers (blue ovals) to regulate Nkx2‐2 expression (representation of the Pax1‐Nkx2‐2 alleles adapted from Ref ; TAD data from Ref ).
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The TZ (transition zone) organizes the regulatory activity of the Bmp7/Tfap2c locus by maintaining two different conformations (Ref ). This confines the action of one enhancer (e.g., forebrain) on the gene in the other domain (e.g., Bmp7), as shown for heart (top panel) and lateral forebrain expression (middle panel). In the medial forebrain (bottom panel), the TZ may control the strength of Bmp7 promoter competition for the forebrain enhancer.
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