Phd Position in Molecular and Computational Neurogenomics

**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 most prominent 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, 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 identify key regulatory factors governing cell-type specific response to CMT-causing mutations. Finally, we will validate the identified key (epi)genetic molecular and explore their therapeutic potential in vitro and in vivo disease models.

**Profile**:

- have an MSc in Systems Biology, Molecular Biology, Natural Sciences or related disciplines
- be very motivated and enthusiastic to learn and expand both computational and experimental skill set
- have an analytical mindset
- be able to summarize data extracted from the literature and shape research objectives
- be able to communicate with experimental and computational scientists efficiently
- have excellent communication and writing skills in English

**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

**We offer**:
As part of the VIB-UAntwerp Center for Molecular Neurology and VIB, the applicant will benefit from established collaborations and access to centralized facilities with expertise in genomics, functional genomics and cell biology, proteomics, cutting-edge microscopy, structural biology, technology development, and bioinformatics.

VIB provides a highly interactive environment and ample training opportunities for its researchers. In addition, the VIB-UAntwerp Center for Molecular Neurology is located in the city of Antwerp, the capital of Flanders, offering a culturally and historically rich and ethnically diverse environment.

The VIB-UAntwerp Center for Molecular Neurology has 7 PIs and hosts internationally recognized leaders in Neurogenetics and Neuroinflammation. Current research groups address a broad set of questions related to neurodegenerative diseases of the central and peripheral nervous system, emphasizing understanding the genetic etiology and developing diagnostics and treatment methods. Approaches range from human genetics, genomics, protein biochemistry and neuronal and glial cell biology to integrative systems and computa