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Understanding the impact of DNA demethylation in Motor Neuron Disorders

Project description

Insight into the epigenetic profile of motor neuron disorders

Motor neuron disorders (MND), comprising spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), are a group of devastating diseases mainly manifested by motor neuron degeneration. Emerging evidence suggests that disease severity is modulated through epigenetics in which DNA methylation plays a dominant role. The scope of the EU-funded MANTIS project is to uncover the epigenetic mechanism gone awry in MND. Leveraging cutting-edge techniques from next-generation sequencing to single-cell mass cytometry and patient-derived iPSCs, the scientists will explore the role of the ten-eleven translocation (TET) enzymes. In DNA methylation, TETs are responsible for balancing the hydroxymethylated cytosines (5hmC) to favor gene expression. The therapeutic potential of demethylation will also be explored to correct the epigenetic profile and restore the disrupted gene expression.

Objective

Motor neuron disorders (MND) are a spectrum of devastating diseases caused by motor neuron (MN) cell death. Recent findings revealed that DNA methylation is a hallmark of MN cell death. However, the cause and affected mechanisms leading to methylation increase remain mostly unknown, therefore limiting the design of therapeutic intervention. The discovery of a novel DNA modification has provided a paradigm shift in the understanding of DNA methylation and demethylation regulatory network. In fact, methylated cytosines (5mC) can be converted to hydroxymethylated cytosines (5hmC) by Ten-eleven-translocation (TET) enzyme family. 5hmC is found to be stably present in DNA and to influence gene expression as an epigenetic mark independent of 5mC. My preliminary experiments showed that MN death in a severe mouse model of Spinal Muscular Atrophy (SMA) is correlated to a genome-wide increase in 5mC levels and loss of 5hmC. This research proposal therefore aims to define the role of 5hmC and the TET family of enzymes in controlling MN pathophysiology. To address the common role of DNA demethylation loss in MND, I will investigate the methylation mechanism in SMA and another MND- Amyotrophic lateral sclerosis (ALS). The specific aims of this project are to (1) define the exact profile of 5mC and 5hmC in regulating gene expression in SMA and ALS via a genome-wide reduced representation sequencing; (2) test whether TETs interact with the Survival of Motor Neuron (SMN1) protein that is responsible for MNs cell death in SMA; (3) establish the therapeutic potential of a locus-specific demethylation in promoting restoration of the diseased epigenetic profile using the Crispr/Cas9 technology. These studies will greatly advance the understanding of the epigenetic regulation of MN cell death by 5hmC and TET proteins, and will set the stage for testing the therapeutic potential of these novel regulators in MNs disorders.

Coordinator

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Net EU contribution
€ 196 707,84
Address
RUE DE TOLBIAC 101
75654 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 196 707,84