Denis Duboule | EPFL Graph Search

Denis Duboule is born in 1955 and is both swiss and french national. He studied biology at the university of Geneva, where he obtained a PhD in mammalian embryology in 1984. He then spent 10 years abroad, first as a group leader in the medical faculty in Strasbourg (France), then at the European Laboratory for Molecular Biology (EMBL) in Germany. In 1993, he was appointed full professor at the university of Geneva, where he chairs the department of Genetics and Evolution ever since 1997. In 2001, he chaired the national center of research Frontiers in Genetics and in 2012 the division III of the SNSF. In 2006, he was appointed full professor at the federal institute of technology (EPFL) in Lausanne, where he leads the laboratory of Developmental Genomics (UpDUB).

His research activities are in the fields of embryology, genetics and developmental genomics of mammals, in an evolutionnary context. In particular, his laboratory has been closely associated with the structural and functional studies of mammalian Hox genes, by using mouse molecular genetic approaches. Duboule is also active in the communication of science, is member of the Academia Europea as well as of several academies in Switzerland, France and the Netherland. He is a foreign member of the Royal Society (UK) and of the National Academy of Sciences USA. He has received various scientific prizes and awards, amongst which the Marcel Benoist Prize, the Louis-Jeantet prize for medicine in 1998 or the international INSERM prize in 2010 (see also https://en.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

Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae

Denis Duboule, Aurélie Hintermann, Jozsef Zakany

In the course of evolution, pecorans (i.e., higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as "headgear," which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae.

OXFORD UNIV PRESS2021

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