1. Large scale genomic reorganization of topological domains at the HoxD locus
- Author
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Daan Noordermeer, Pierre J. Fabre, Lucille Lopez-Delisle, Benjamin H. Mormann, Leonardo Beccari, Marion Leleu, Denis Duboule, School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Dynamique de la Chromatine (CHRODY), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Neurobiologia Molecular Celular y del desarrollo, Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-CIBER de Enfermedades Raras (CIBERER), Chaire internationale Évolution des génomes et développement, Collège de France (CdF (institution)), Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Centro de Biologia Molecular Severo Ochoa (CBMSO)-CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), and Collège de France - Chaire internationale Évolution des génomes et développement
- Subjects
0301 basic medicine ,Chromatin Immunoprecipitation ,Genomic Islands ,Transcription, Genetic ,lcsh:QH426-470 ,[SDV]Life Sciences [q-bio] ,Locus (genetics) ,Regulatory Sequences, Nucleic Acid ,Biology ,Topology ,Chromosome conformation capture ,Mice ,03 medical and health sciences ,Chromatin organization ,Animals ,Hox gene ,Enhancer ,lcsh:QH301-705.5 ,In Situ Hybridization, Fluorescence ,Limb development ,Gene Rearrangement ,Topologically associating domains ,Research ,Genes, Homeobox ,High-Throughput Nucleotide Sequencing ,Genomics ,TAD ,Gene rearrangement ,CTCF ,Hox ,Gene regulation ,Chromatin ,lcsh:Genetics ,Enhancer Elements, Genetic ,030104 developmental biology ,lcsh:Biology (General) ,Genetic Loci ,Multigene Family ,Chromatin immunoprecipitation ,Regulatory landscape - Abstract
Background The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts. Results To assess the structure–function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters. Conclusions Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1278-z) contains supplementary material, which is available to authorized users.
- Published
- 2017
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