title: The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances.
abstract: Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs). Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Importantly, changing intra-TAD distances had no impact on Shh expression. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods.
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Symmons
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Leslie
authors.initials: L
authors.lastname: Pan
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Remeseiro
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Tugce
authors.initials: T
authors.lastname: Aktas
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Klein
authors.affiliation: Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: Developmental Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany; Genome Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. Electronic address: francois.spitz@pasteur.fr.
authors.forename: François
authors.initials: F
authors.lastname: Spitz
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000196:embryology / Q000235:genetics; D004742:Enhancer Elements, Genetic; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D053823:Hedgehog Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse
keywords: Shh; chromatin conformation; gene expression; long-distance enhancers; topological domains