Epigenetic insights into the non-coding genome in neurodegenerative diseases

About the Project

This PhD explores the role of the emerging field of retrotransposons within the non-coding genome and their impact on neurodegenerative diseases, focusing on epigenetic regulation and revealing insights into how these elements confer risk for development and progression of motor neurone disease. A unique aspect is the generation of a novel liquid biopsy for the generation of new biomarkers for use in the diagnosis and prognosis of motor neurone disease with close collaboration with colleagues at the University of Exeter.

This PhD project will investigate the role of non-coding DNA elements in the human genome, which are strongly associated with the risk and progression of various neurodegenerative disorders, including Motor Neurone Disease (MND). The primary focus will be on the epigenetic regulation of these elements, aiming to elucidate the fundamental mechanisms governing their control and their impact on gene function and disease risk.

The project will require collaboration with clinical and academic collaborators within the Walton Centre NHS foundation trust and the University of Exeter. Clinical samples from individuals with MND will be collected and processed to isolate small fragments of DNA called circulating cell free DNA (cfDNA) which are released from dying cells within the central nervous system. In partnership with the University of Exeter, the project will analyse and quantify cfDNA to determine the origin of central nervous system cells from human plasma samples, establishing a pioneering novel liquid biopsy approach for early detection of neurodegeneration in MND. Utilising Oxford Nanopore Technologies (ONT) sequencing platforms, the research will assess genomic variation in cfDNA, including retrotransposable elements and variable number tandem repeats, an emerging source of genetic risk in MND. This combined genetic and epigenetic strategy aims to develop a highly sensitive test to detect neuronal loss in early stages of MND, enabling timely therapeutic intervention, disease stratification, and enhanced clinical trial design.

The project will also establish multiple laboratory models and assays to explore and validate the findings of the cfDNA analysis as well as fundamental cell-based models. Techniques such as CRISPR, RNA-seq, Oxford Nanopore Technologies (ONT) sequencing for structural variant and methylation analysis, chromatin immunoprecipitation sequencing (ChIP-seq), chromatin architecture assays such as Hi-C and Omni-C, and polymerase chain reaction (PCR) approaches will be employed. Based cfDNA analysis results, specific retrotransposable elements of interest will be targeted to develop cellular models of neurodegeneration, and comprehensive analyses will be conducted to assess the genomic functional effects of each targeted element.

Throughout the project, the candidate will develop both technical and professional skills by designing and executing experimental protocols, analysing data, and presenting research findings. Opportunities will be available to attend local and international conferences to discuss and present research through oral and poster presentations to a global audience. Active engagement in professional development and participation with the research community are essential for cultivating a comprehensive skill set and advancing as a scientist.