Denis Duboule | EPFL Graph Search

Denis Duboule est né en 1955. De Nationalités Suisse et Française, il étudie la biologie à lUniversité de Genève où il reçoit un PhD dans le domaine de lembryologie des mammifères en 1984. Il passe ensuite 10 ans à létranger, dabord comme post-doc et group leader à la faculté de Médecine de Strasbourg (CNRS), puis au Laboratoire Européen de Biologie Moléculaire, à Heidelberg (Allemagne). En 1993, il est nommé Professeur ordinaire à lUniversité de Genève, où il dirige le département de Génétique et Evolution depuis 1997. En 2001 il prend la direction du pôle dexcellence NCCR aux Frontières de la Génétique et celle de la division médecine-Biologie du FNS en 2012. En 2006, il est nommé Professeur ordinaire à lEPFL, Lausanne, où il dirige le laboratoire de Génomique du Développement (UpDUB).

Ses activités de recherche sexercent dans le domaine de lembryologie, de la génétique et de la génomique du développement des mammifères, dans le contexte général de lEvolution des structures et des organes. En particulier, son laboratoire a été associé à de nombreuses recherches dans le domaine de lanalyse structurelle et fonctionnelle des gènes architectes (Hox) et de leur régulation transcriptionnelle pendant le développement précoce. Denis Duboule est également actif dans le domaine de la communication de la science. Il est membre de lAcademia Europea ainsi que dautres académies. Il est également membre de lInstitut de France (Académie des Sciences), de la Société Royale (UK) et de lAcadémie des Sciences Américaine (NAS). Il a reçu plusieurs prix et distinction, notamment le Prix Marcel Benoist, le Prix Louis-Jeantet de Médecine en 1998 et le Prix international de lINSERM en 2010. Voir également https://fr.wikipedia.org/wiki/Denis_Duboule.

Context-dependent enhancer function revealed by targeted inter-TAD relocation

Guillaume Andrey, Christopher Chase Bolt, Lucille Delisle, Denis Duboule, Aurélie Hintermann

Here the authors show that a strong enhancer sequence can be controlled by the chromatin environment provided by a topologically associated domain (TAD) located nearby. An enhancer relocated by homologous recombination takes all the hallmarks of its new neighboring enhancers located in the recipient TAD. The expression of some genes depends on large, adjacent regions of the genome that contain multiple enhancers. These regulatory landscapes frequently align with Topologically Associating Domains (TADs), where they integrate the function of multiple similar enhancers to produce a global, TAD-specific regulation. We asked if an individual enhancer could overcome the influence of one of these landscapes, to drive gene transcription. To test this, we transferred an enhancer from its native location, into a nearby TAD with a related yet different functional specificity. We used the biphasic regulation of Hoxd genes during limb development as a paradigm. These genes are first activated in proximal limb cells by enhancers located in one TAD, which is then silenced when the neighboring TAD activates its enhancers in distal limb cells. We transferred a distal limb enhancer into the proximal limb TAD and found that its new context suppresses its normal distal specificity, even though it is bound by HOX13 transcription factors, which are responsible for the distal activity. This activity can be rescued only when a large portion of the surrounding environment is removed. These results indicate that, at least in some cases, the functioning of enhancer elements is subordinated to the host chromatin context, which can exert a dominant control over its activity.

NATURE PORTFOLIO2022

Induction of a chromatin boundary in vivo upon insertion of a tad border

Christopher Chase Bolt, Lucille Delisle, Denis Duboule, Marie-Laure Gadolini, Edgardo Rodriguez Carballo

Author summary During development, enhancer sequences tightly regulate the spatio-temporal expression of target genes often located hundreds of kilobases away. This complex process is made possible by the folding of chromatin into domains, which are separated from one another by specific genomic regions referred to as boundaries. In order to understand whether such boundary sequences require their particular genomic contexts to achieve their isolating effect, we analyzed the impact of introducing one such boundary, taken from the HoxD gene cluster, into a distinct topological domain. We show that this ectopic boundary splits the host domain into two sub-domains and affect the expression levels of a neighboring gene. We conclude that this sequence can work independently from its genomic context and thus carries all the information necessary to act as a boundary element. Mammalian genomes are partitioned into sub-megabase to megabase-sized units of preferential interactions called topologically associating domains or TADs, which are likely important for the proper implementation of gene regulatory processes. These domains provide structural scaffolds for distant cis regulatory elements to interact with their target genes within the three-dimensional nuclear space and architectural proteins such as CTCF as well as the cohesin complex participate in the formation of the boundaries between them. However, the importance of the genomic context in providing a given DNA sequence the capacity to act as a boundary element remains to be fully investigated. To address this question, we randomly relocated a topological boundary functionally associated with the mouse HoxD gene cluster and show that it can indeed act similarly outside its initial genomic context. In particular, the relocated DNA segment recruited the required architectural proteins and induced a significant depletion of contacts between genomic regions located across the integration site. The host chromatin landscape was re-organized, with the splitting of the TAD wherein the boundary had integrated. These results provide evidence that topological boundaries can function independently of their site of origin, under physiological conditions during mouse development.

PUBLIC LIBRARY SCIENCE2021

Induction of a chromatin boundary in vivo upon insertion of a tad border

Christopher Chase Bolt, Lucille Delisle, Denis Duboule, Marie-Laure Gadolini, Edgardo Rodriguez Carballo

PUBLIC LIBRARY SCIENCE2021