PROJECT DESCRIPTION

We are a highly motivated international team of researchers at the Molecular Neurogenomics group (Jordanova Lab) and the Computational Neurobiology group (Malysheva Lab) at the VIB CMN. We are excited to announce a call for a joint PhD student in our labs to work on a challenging project at the interface of neurodegeneration, genomics, computational and systems biology.
Charcot-Marie-Tooth disease (CMT) represents the most common genetic disorder of the peripheral nervous system. Patients experience progressive distal muscle weakness and wasting, sensory loss, and skeletal deformities ultimately leaving them severely disabled. This lifelong disorder is currently incurable. The largest protein family implicated in the etiology of CMT are aminoacyl-tRNA synthetases (ARS). Ubiquitous and essential enzymes, ARS catalyse a critical step in protein biosynthesis by charging tRNA with their cognate amino acid. Jordanova Lab reported that dominant mutations in the tyrosyl-tRNA synthetase (YARS) cause a clinical variant of CMT and so far six additional cytoplasmic ARS have been implicated in the same pathology.
The overarching goal of this proposal is to understand why and how dysregulation of omnipresent and constantly expressed ARS proteins leads to dying-back neurodegeneration and affects specifically the peripheral neurons (PNs). This neuronal population contains the most polarized cells in our body and their sophisticated morphology and function render them highly susceptible to degeneration. The preliminary data generated in-house as well as the available public data suggest mechanisms involving genetic, epigenetic and chromatin organisation factors governing the cell-type specific response to ARS mutations. Therefore, an integrative genome-wide cis-regulatory network analysis approaches, developed and employed in the Malysheva Lab, are required to reveal these mechanisms.
With the proposed project we aim to bridge this gap in our knowledge of cis-regulatory mechanisms underlying this disease and reveal the mechanisms underlying the strong cell-type specific effect of the CMT-causing YARS mutations. For this we will generate high-resolution spatial chromatin organisation, chromatin accessibility and gene expression data for all major cell types forming the peripheral nerve environment (as well as controls), generated from the patient-derived iPSCs and integrate these data into the cis-regulatory networks. Following cis-GRN network reconstruction and formal graph analysis, we will identified key regulatory factors governing cell-type specific reponse to CMT-causing mutations. Finally, we will validate the identified key (epi)genetic molecular and eplore their therapeutic potential in in vitro and in vivo disease models.

REQUIRED SKILLS

• confident in basic molecular biology techniques, such as cell cultures, basic genomics data generation
• knowledge of (theory behind) gene regulatory mechanisms and multimodal data integration
• basic/intermediate programming skills in R and/or Python
• Ability to adapt to the research environments while being full members of two labs

DESIRABLE SKILLS

• statistical analysis
• basic processing of NGS data
• experience with iPSC and/or cell culturing
• knowledge of and some experience with genetic perturbation assays, such as CRISPR

Please refer the Job description for details