A challenging postdoctoral position that will use innovative (high-throughput) genome editing tools to study how dysfunctions at the level of DNA and RNA regulatory elements drives toxic cellular phenotypes in amyotrophic lateral sclerosis (ALS) using advanced human in vitro systems. You will have the opportunity to play a pivotal role in a multi-disciplinary team that connects large scale genomic analyses of patients with detailed functional experiments using iPSC-based in vitro modelling.
Your research will focus on decoding cell specific regulatory codes that are vulnerable to toxic risk factors in ALS - a fatal neurodegenerative disorder that affects 1 in 350 people. These regulatory codes are determined by functional elements that act at the level of either DNA or RNA to ensure correct expression, post-transcriptional processing and/or localization of key mRNA transcripts. It is already known that a failure in the maintenance of such regulatory codes is key to pathological events in both laboratory models of ALS and patients. Recent work by the project supervisors has provided new insights into this through multi-omic single cell analyses of patient tissue, large scale human genetics studies and transcriptomic analyses of novel ALS iPSC models. However, innovative and scalable technologies are needed to bridge key knowledge gaps and to connect prioritized DNA / RNA regulatory elements with functional outcomes in neural cell types. These relationships will need to be characterized at single cell resolution and interpreted in an isoform-specific manner. To fulfil these needs, you will implement a CRISPR based screening approach to manipulate key regulatory targets that have been prioritized using existing transcriptome, epigenome and genetic datasets from ALS patients. Your objective will be to quickly extend from low throughput evaluation of high priority targets in simple cell lines, to higher throughput investigations conducted using disease relevant iPSC models. Your work will be supported by interactions with colleagues that can provide the necessary supporting expertise in ALS, bioinformatics, genomics and iPSC models.