title: Clustering of tissue-specific sub-TADs accompanies the regulation of HoxA genes in developing limbs.
abstract: 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.
authors.affiliation: Unité de génétique et développement, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
authors.forename: Soizik
authors.initials: S
authors.lastname: Berlivet
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Paquette
authors.affiliation: Unité de génétique et développement, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Dumouchel
authors.affiliation: Unité de génétique moléculaire, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langlais
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
authors.affiliation: Unité de génétique et développement, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada ; Department of Medicine, University of Montréal, Montréal, Québec, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Kmita
mesh_terms: D000818:Animals; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005121:Extremities / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D014158:Transcription, Genetic; D014714:Vertebrates / Q000235:genetics / Q000254:growth & development
chemical_list: D018398:Homeodomain Proteins; C486697:Hoxd1 protein, mouse; C088144:HoxA protein