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Collinear regulation of HoxD genes during development and evolution

English title Collinear regulation of HoxD genes during development and evolution
Applicant Duboule Denis
Number 155863
Funding scheme Project funding (Div. I-III)
Research institution Département de Génétique et Evolution Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Embryology, Developmental Biology
Start/End 01.11.2014 - 31.10.2017
Approved amount 1'024'488.00
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Keywords (5)

evolution; Hox genes; epigenetics; tetrapods; transcription

Lay Summary (French)

Lead
REGULATION DES GENES HOX PENDANT LE DEVELOPPEMENT DES MAMMIFERES
Lay summary

Ce travail concerne le contrôle transcriptionnel des gènes Hox, c’est à dire l’étude des mécanismes qui dirigent l’expression de ces gènes pendant le développement embryonnaire. Les gènes Hox sont d’une importance particulière pour l’organisation générale du plan du corps pendant l’embryogenèse et il est donc crucial que chacun de ces 39 gènes fonctionne au bon moment et dans le tissue approprié. Comment cela marche-t-il ? Quelle est la nature intime des processus qui gouvernent avec précision ces activations ? La compréhension de ces questions clés nous informera également sur l’évolution de ces systèmes génétiques, soit sur l’évolution de notre propre embryologie. Pour étudier ces questions complexes, nous utilisons un portfolio de technologies génétiques qui nous permettent d’analyser avec une grande précision ce qui se passe lorsque les environnements génomiques des gènes Hox sont modifiés. De cette façon, nous pouvons déterminer et isoler les morceaux d’ADN nécessaires à la bonne régulation de ces gènes et qui agissent soit en les activant, soit en les réprimant.

En utilisant ces approches génétiques chez la souris de laboratoire, nous pouvons produire des animaux par simples croisements, qui porteront soit des délétions, des duplications, des inversions ou des translocations dans leurs ADN. Ces nombreux stocks de souris transgéniques mutantes dans lesquelles les environs des gènes Hox sont modifiés nous permettent, en analysant leurs effets, de mieux comprendre la nature des paysages de régulations de notre ADN. Ces expériences révéleront donc des éléments importants de l’architecture de notre génome, en particulier de la relation structure-fonction de notre chromatine dans les mécanismes de régulation génétiques, ceux-là même qui sont souvent perturbés dans nombre de syndromes génétiques chez les humains.

Direct link to Lay Summary Last update: 27.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes
Rodriguez-Carballo Eddie, Lopez-Delisle Lucille, Zhan Ye, Fabre Pierre J., Beccari Leonardo, El-Idrissi Imane, Ozadam Hakan, Dekker Job, Duboule Denis (2017), The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes, in GENES & DEVELOPMENT, 31(22), 2264-2281.
Control of growth and gut maturation by &ITHoxD&IT genes and the associated lncRNA &ITHaglr&IT
Zakany Jozsef, Darbellay Fabrice, Mascrez Benedicte, Necsulea Anamaria, Duboule Denis (2017), Control of growth and gut maturation by &ITHoxD&IT genes and the associated lncRNA &ITHaglr&IT, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114(44), 9290-9299.
Large scale genomic reorganization of topological domains at the HoxD locus
Fabre Pierre J., Leleu Marion, Mormann Benjamin H., Lopez-Delisle Lucille, Noordermeer Daan, Beccari Leonardo, Duboule Denis (2017), Large scale genomic reorganization of topological domains at the HoxD locus, in GENOME BIOLOGY, 18, 1-3.
Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock
Deschamps Jacqueline, Duboule Denis (2017), Embryonic timing, axial stem cells, chromatin dynamics, and the Hox clock, in GENES & DEVELOPMENT, 31(14), 1406-1416.
Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells
Rodrigues Alan R., Yakushiji-Kaminatsui Nayuta, Atsuta Yuji, Andrey Guillaume, Schorderet Patrick, Duboule Denis, Tabin Clifford J. (2017), Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114(12), 3139-3144.
Hotair Is Dispensible for Mouse Development
Amandio Ana Rita, Necsulea Anamaria, Joye Elisabeth, Mascrez Beaneadicte, Duboule Denis (2016), Hotair Is Dispensible for Mouse Development, in PLOS GENETICS, 12(12), 1-3.
Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci
Darbellay Fabrice, Duboule Denis (2016), Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci, in ESSAYS ON DEVELOPMENTAL BIOLOGY, PT A, 116, 299-306.
Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape
Schep Ruben, Necsulea Anamaria, Rodriguez-Carballo Eddie, Guerreiro Isabel, Andrey Guillaume, Huynh Thi Hanh Nguyen, Marcet Virginie, Zakany Jozsef, Duboule Denis, Beccari Leonardo (2016), Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(48), 7720-7729.
Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan
Guerreiro Isabel, Gitto Sandra, Novoa Ana, Codourey Julien, Gonzalez Federico, Milinkovitch Michel C., Mallo Moises, Duboule Denis (2016), Reorganisation of Hoxd regulatory landscapes during the evolution of a snake-like body plan, in ELIFE, 5, 1-3.
A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus
Beccari Leonardo, Yakushiji-Kaminatsui Nayuta, Woltering Joost M., Necsulea Anamaria, Lonfat Nicolas, Rodriguez-Carballo Eddie, Mascrez Benedicte, Yamamoto Shiori, Kuroiwa Atsushi, Duboule Denis (2016), A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus, in GENES & DEVELOPMENT, 30(10), 1172-1186.
Tetrapod axial evolution and developmental constraints; Empirical underpinning by a mouse model
Woltering Joost M., Duboule Denis (2015), Tetrapod axial evolution and developmental constraints; Empirical underpinning by a mouse model, in MECHANISMS OF DEVELOPMENT, 138, 64-72.
Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states
Fabre Pierre J., Benke Alexander, Joye Elisabeth, Manley Suliana, Duboule Denis (2015), Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(45), 13964-13969.
Structure, function and evolution of topologically associating domains (TADs) at HOX loci
Lonfat Nicolas, Duboule Denis (2015), Structure, function and evolution of topologically associating domains (TADs) at HOX loci, in FEBS LETTERS, 589(20), 2869-2876.
Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain
Vieux-Rochas Maxence, Fabre Pierre J., Leleu Marion, Duboule Denis, Noordermeer Daan (2015), Clustering of mammalian Hox genes with other H3K27me3 targets within an active nuclear domain, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(15), 4672-4677.
Snakes: hatching of a model system for Evo-Devo?
Guerreiro Isabel, Duboule Denis (2014), Snakes: hatching of a model system for Evo-Devo?, in INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY, 58(10-12), 727-732.
Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci
Lonfat Nicolas, Montavon Thomas, Darbellay Fabrice, Gitto Sandra, Duboule Denis (2014), Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci, in SCIENCE, 346(6212), 1004-1006.
Long-range regulation and enhancer hi-jacking at Hox gene clusters
Duboule D. (2014), Long-range regulation and enhancer hi-jacking at Hox gene clusters, in FEBS JOURNAL, 281, 28-29.
Considerations when investigating IncRNA function in vivo
Bassett Andrew R., Akhtar Asifa, Barlow Denise P., Bird Adrian P., Brockdorff Neil, Duboule Denis, Ephrussi Anne, Ferguson-Smith Anne C., Gingeras Thomas R., Haerty Wilfried, Higgs Douglas R., Miska Eric A., Ponting Chris P. (2014), Considerations when investigating IncRNA function in vivo, in ELIFE, 3, 1-3.
Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs
Lopez-Rios Javier, Duchesne Amandine, Speziale Dario, Andrey Guillaume, Peterson Kevin A., Germann Philipp, Uenal Erkan, Liu Jing, Floriot Sandrine, Barbey Sarah, Gallard Yves, Mueller-Gerbl Magdalena, Courtney Andrew D., Klopp Christophe, Rodriguez Sabrina, Ivanek Robert, Beisel Christian, Wicking Carol, Iber Dagmar, Robert Benoit, McMahon Andrew P., Duboule Denis, Zeller Rolf (2014), Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs, in NATURE, 511(7507), 46-46.
Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci
Noordermeer Daan, Leleu Marion, Schorderet Patrick, Joye Elisabeth, Chabaud Fabienne, Duboule Denis (2014), Temporal dynamics and developmental memory of 3D chromatin architecture at Hox gene loci, in ELIFE, 3, 1-3.
Evolving Hox Activity Profiles Govern Diversity in Locomotor Systems
Jung Heekyung, Mazzoni Esteban O., Soshnikova Natalia, Hanley Olivia, Venkatesh Byrappa, Duboule Denis, Dasen Jeremy S. (2014), Evolving Hox Activity Profiles Govern Diversity in Locomotor Systems, in DEVELOPMENTAL CELL, 29(2), 171-187.
SnapShot: Hox Gene Regulation
Andrey Guillaume, Duboule Denis (2014), SnapShot: Hox Gene Regulation, in CELL, 156(4), 1-2.
Conservation and Divergence of Regulatory Strategies at Hox Loci and the Origin of Tetrapod Digits
Woltering Joost M., Noordermeer Daan, Leleu Marion, Duboule Denis (2014), Conservation and Divergence of Regulatory Strategies at Hox Loci and the Origin of Tetrapod Digits, in PLOS BIOLOGY, 12(1), 1-3.

Collaboration

Group / person Country
Types of collaboration
Manley/EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Milinkovitch/Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Mundlos/Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dasen/NYU USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dekker/Boston United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Awards

Title Year
Denis Duboule was nominated as a Professor at the Collège de France 2017

Associated projects

Number Title Start Funding scheme
122008 Hox genes and the molecular bases of vertebrate development 01.10.2008 Project funding (Div. I-III)
189956 engineering gastruloids to study the impact of mechanical constraints upon mammalian development 01.02.2020 Sinergia
164106 Multicolour 3D STED Microscope 01.12.2015 R'EQUIP
176395 Collinear regulation of HoxD genes during development and evolution 01.11.2017 Project funding (Div. I-III)

Abstract

This grant application is the continuation of our previous work on the mechanistic nature of collinear gene regulation at Hox loci. It is concerned with the elucidation of those mechanisms underlying the long-range and coordinated transcriptional control of clusters of Hox genes. The ultimate aim of this research is to understand the origin, evolution and implementation of collinear Hox gene regulation in two different developmental contexts, the major axis and the appendicular axis. Several approaches are used, all relying on mammalian and molecular genetics and generally based on the large amount of mutant stocks we accumulated during the last three rounds of SNF funding. In summary, we would like to look at the importance of both the distribution of ‘epigenetic’ chromatin marks and the presence of natural or artificial antisense RNAs in the control of collinearity. We also would like to assess the respective weights of cluster-internal versus external factors in this critical regulation during trunk extension by using range of deletions and inversions affecting the flanking gene deserts, as well as to see the behavior of Hox gene clusters from other species implementing collinearity with some differences, whenever Hox clusters are introduced into the mouse. In the case of the limbs, where the mechanisms are likely distinct, we want to directly visualize its implementation by 3D-DNA FISH. We also want to analyze the situation into two different types of animals with various limb morphologies (with respect to the relative position of the mesopodium) to see if our recent understanding of the mouse mechanism can be integrated into an evolutionary framework, i.e. if our recent work has a heuristic value when thinking about the evolution of vertebrate limbs
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