title: A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus.
abstract: During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.
authors.affiliation: Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Leonardo
authors.initials: L
authors.lastname: Beccari
authors.affiliation: School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Nayuta
authors.initials: N
authors.lastname: Yakushiji-Kaminatsui
authors.affiliation: Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Joost M
authors.initials: JM
authors.lastname: Woltering
authors.affiliation: School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Anamaria
authors.initials: A
authors.lastname: Necsulea
authors.affiliation: School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lonfat
authors.affiliation: Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Eddie
authors.initials: E
authors.lastname: Rodríguez-Carballo
authors.affiliation: Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland;
authors.forename: Benedicte
authors.initials: B
authors.lastname: Mascrez
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuroiwa
authors.affiliation: Department of Genetics and Evolution, University of Geneva, 1211 Geneva 4, Switzerland; School of Life Sciences, Federal Institute of Technology, Lausanne, 1015 Lausanne, Switzerland;
authors.forename: Denis
authors.identifier: 0000-0001-9961-2960
authors.initials: D
authors.lastname: Duboule
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D002642:Chick Embryo; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005801:Genes, Homeobox / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D017880:Limb Deformities, Congenital / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins
keywords: ankle; polycomb; regulatory landscapes; topologically associating domains (TADs); vertebrate limbs; wrist