Awardees

Supervised by Jérôme D. Robin

Telomeres are nucleoprotein complexes located at the ends of chromosomes. In Human, telomeres consist of a _T2AG3 repeated motif that shortens with each cell division throughout lifespan. Critically short telomeres lose their protective function and lead to cells senescence, apoptosis or early stages of cancer. Additionally, as telomeres shorten, changes in gene expression and epigenetic equilibrium are triggered in two ways: Telomere Position Effect (TPE) and Telomere Position Effect Over Long Distances (TPE-OLD). TPE is defined by the spreading of suppressive epigenetic marks over proximal genes whereas TPE-OLD is a phenomenon modulating transcription through 3D chromatin structure involving telomere sequences (DNA loops). We aimed to define TPE-OLD mechanisms and its implication in rare diseases. In order to achieve this, we developed two methods based on long read nanopore sequencing. The first one focuses on the establishment of telomere length on specific chromosomes, while at the same time identifying the methylation status of the subtelomere region (TPE analysis). The second method uses chromatin conformation capture techinques to visualize global TPE-OLD interactions. Altogether, our work holds the potential to reveal novel implication of telomeres in human pathologies.

Dysferlinopathy is the name given to a group of muscle diseases that are caused by mutations in DYSF gene. Dysferlinopathy has two major phenotypes, "Miyoshi muscular dystrophy 1 (MMD1)" and "Limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2)". In these two phenotypes, even though the causal gene is the same, the initial symptoms and the progress of the disease are different. In MMD1, the muscles farther from the torso (hands and feet) are affected first, in contrast, in LGMDR2, the proximal muscles, the muscles close to the torso are affected first. Understanding the mechanisms that underlie the differences in phenotypes will be helpful in diagnostics of the disease, foreseeing the progress, improving the existing treatments and discovering new ones. For this purpose, we - Ozan Ozisik, Mathieu Cerino, Marc Bartoli and Anaïs Baudot - aimed to identify the genes and mutations that can lead to one phenotype or the other in dysferlinopathy using both the genetic data of the dysferlinopathy patients and the curated knowledge on other muscle diseases.

This research aimed to better understand the link between inflammation and mitochondrial dysfunction in Chagas disease cardiomyopathy (CCC). This neglected disease is caused by the parasite Trypanosoma cruzi and it affects people from Europe, North and South America (where it is endemic). The heart of CCC patients is an inflammatory milieu, rich of interferon-gamma (IFN-γ) and tnf-alpha (TNF-α), which cause damage to the heart, impairing blood pump. Indeed, CCC patients have lower survival rate compared to patients with other cardiomyopathies. Previous data of our group revealed an accumulation of polymorphisms in mitochondrial genes in CCC patients and we raised the hypothesis that mitochondrial dysfunction and excessive inflammation play together to damage the cardiac cells (cardiomyocytes) and thus worsening the disease. In this work, we found that the hearts of CCC patients have decreased number of mitochondrial DNA and higher quantity of nitrite and nitrotyrosine, markers of nitro-oxidative stress. In a similar manner, cardiac cells exposed to IFN-γ and TNF-α have also increased nitro-oxidative stress and decreased number of mitochondrial DNA. Additionally, the cytokines also impaired mitochondrial function of cardiac cells, as observed in changes of oxygen consumption and depleted ATP production. This work provides relevant data to support association between mitochondria dysfunction and CCC, reinforcing new studies targeting mitochondria as a novel strategy for CCC therapy.

Key words: Spinal Cord, MRI, Amyotrophic Lateral Sclerosis, (Ultra) High Field, Longitudinal
Follow-up

This project focuses on the evaluation of early tissue impairment encountered in the context of Amyotrophic Lateral Sclerosis by taking advantages of potentialities offered by both ultra-high field Magnetic Resonance Imaging (7T) and electrophysiological measurements. The project is based on the already existing close collaboration between CRMN-SLA (Pr. S. Attarian and Dr. A. Verschueren) and CRMBM-CEMEREM (V. Callot's team).