Research projects selected by FNRS
5 GIGA projects have just been selected by the FNRS. Congratulations to the project leaders!
Cancer-specific subversion of mRNA degradation pathways by a Prion-like oncogenic transcription factor unravels a new vulnerability in Ewing sarcoma
Ewing sarcomas (EwS) are highly aggressive pediatric cancers with only 50 to 70% of survival 5 years after diagnostic, mainly due to metastasis and lack of targeted therapy. EwS are typified by chromosomal translocations that produce oncogenic fusion proteins, which are often the only recurrent genetic abnormality. These fusions are the key drivers of disease pathogenesis and are essential for the growth and survival of EwS cells. While the causality of these fusions in EwS is well established, their functions remain poorly understood. To date, EwS fusions have been mostly considered and studied as aberrant transcription factors. In this project, we will assess the provocative hypothesis that in addition to their role in transcription, EwS fusions subvert mRNA degradation pathways to impose a specific transcriptional landscape in EwS cells, that contributes to their role in cancer initiation and progression. We will also test the idea that this new function of EwS fusions provides novel therapeutic opportunities for this rare and still formidable family of malignancies.
ROAGE : Revealing past inbreeding dynamics in animal populations through improved estimation of age of homozygous-by-descent segments and runs-of-homozygosity (ROH)
Homozygous-by-descent (HBD) segments occur when a DNA segment is inherited twice from a common ancestor through different genealogical paths, as a result of inbreeding. These segments appear as long stretches of homozygous genotypes known as runs-of-homozygosity (ROH). ROH are widely used for several applications in animal genomics, including estimating inbreeding coefficients, studying inbreeding depression, assessing genetic diversity, inferring past demography, and identifying selection signatures. The length of ROH is related to the number of generations to the common ancestor (i.e. it indicates the age of the inbreeding event) and can be used to estimate past effective population size (Ne) or to study the relationship between inbreeding age and mutation load. Despite the increasing popularity of these applications, there is still a lack of evaluation of their accuracy. We have recently shown that ZooRoH, a model-based approach we developed, is more efficient in assigning HBD segments to the correct age class. Comparisons with state-of-the-art methods are also lacking for the estimation of past Ne. Here, we will first use simulations to evaluate the accuracy of ZooRoH and ROH-based approaches for estimating the age of HBD segments. We will then implement new methodological features to improve ZooRoH, and develop a new approximate Bayesian computation framework to more accurately estimate past Ne with ROH-based approaches. These new methods will be evaluated on simulated data and on real data from populations with well recorded demographic history, including temporal genomic data. Finally, we will define new parameters derived from the distribution of HBD segments to characterize inbreeding dynamics, and then run ZooRoH on a large number of populations. The inferred parameters will be used to classify the populations into major groups related to their demographic history. This classification approach could then be applied to new populations of unknown status.
Deciphering species-specific mechanisms of neuron migration
Cerebral cortex morphogenesis relies on an exquisite choreography of neural cells that migrate together in shared forebrain area. The project NEUREVODEVO builds upon solid preliminary comparative analyses made across three mammalian species which revealed species-specific patterns of cIN migration. Here, we will consolidate these observations by time-lapse microscopy and further combine single cell analyses with functional experiments to decipher the molecular machinery responsible for singularities in cIN migration in the different species. Our work will shed light on novel evo-devo mechanisms that control cell movement. Furthermore, our pioneer pipeline may help designing better human-based models for drug screening against neurodevelopmental disorders associated with neuron migration defects for which, according to our preliminary data, mouse models might not be ideal.
Impact of insomnia on emotional responses and its cerebral correlates
In the last few years insomnia disorder (ID) has been attracting inscreasing attention due to its huge socioeconomic burden, its prevalence and destructive impact on mental health. Altered emotion regulation may not only result from ID but also constitutes a risk factor for its development. However, a consensus about ID-related alteration in the functional brain circuitry underlying emotion regulation has not yet been reached, putatively due to heterogeneity in the expression and development of the disease. Furthermore, whether and how ID affects sleep-dependent overnight emotional adaptation remains underexplored, even though ID has been suggested to go along with restless rapid eye movement (REM) sleep, which appears crucial for such adaptive response. In this study, we will assess behavioural and cerebral responses to emotional stimuli in homogenous samples of ID patients based on a recently suggested ID subtyping. Contrary to previous studies that predominantly assessed the instant brain activation underlying emotion regulation by using a regional cortical approach, we will use magnetic resonance imaging (MRI) to probe ID-related differences in functional connectivity of emotional brain responses and the implication of the arousal and REM sleep regulating subcortical locus coeruleus (LC). We will further assess the impact of ID on the overnight adaptive response in the salience network and limbic circuit. We expect decreased activation, altered functional connectivity and less efficient overnight adaptation to emotional distress in ID. We finally hypothesize that these differences will be associated with the degree of electrophysiology-derived REM sleep consolidation, and are mediated by structural and functional LC integrity. The study will provide new evidence on the detrimental impact of restless REM sleep on ID expression and contribute to the understanding of emotion regulation as a mechanism underlying ID.
Role of Mesenchymal Stromal Cells (MSC) during Normothermic Machine Perfusion (NMP) of kidney grafts from donation after circulatory death (DCD)
Expanded PRS embracing pathways and interactions for increased clinical utility
A polygenic risk score (PRS) is a number that summarizes the estimated effect of many genetic variants on an individual's phenotype, typically derived from weights from cross-sectional genome-wide association studies (GWASs) of prevalent disease cases and controls. Clinical implementation of PRS may help inform diagnostics or treatment choices. Higher-end extreme PRS scores for some diseases can approximate risks equivalent to those embodied by clinical risk factors or monogenic disorders. However, more work is needed to increase the discriminative power of PRS in a general population, estimate lifetime risk trajectories, or identify fine-scale substructure in patient populations. This project combines disease knowledge-informed molecular interaction networks with GWAS-induced large-scale epistasis screening to derive novel expanded pathway-PRSs. The outcome is a newly developed composite score composed of 1- and 2-dimensional genetic information and an optimization protocol according to prediction performance and disease subtyping. As a by-product, the project will provide insights into the added value of pathway-oriented epistasis screening and handling complex genetic risk regions.