Human Genetics, Genomics and Disease: Integrating fusion-proteins molecular signatures for advancing sarcoma diagnosis and therapy

Location:     MRC Human Genetics Unit, University of Edinburgh, UK & Max Delbrück Center, Berlin, Germany 

Supervisors: Dr Nezha Benabdallah, Dr Daria Bunina

 Applications are invited from outstanding candidates for an MRC funded 3.5-year international visiting PhD studentship in Human Genetics, Genomics and Disease. This studentship will involve a collaborative research project between the MRC Human Genetics Unit (HGU), part of the Institute of Genetics and Cancer at the University of Edinburgh, UK and the Max Delbrück Center for Molecular Medicine (MDC) in Berlin, Germany. This studentship will be primarily based in HGU at the University of Edinburgh and will involve collaborative research visits to MDC in Berlin. Successful candidates will benefit from high quality training, mentorship, cutting-edge technological infrastructure and research excellence across both institutions to develop their abilities to tackle challenging questions in biomedical research.

Project Outline

Sarcomas are a group of cancers impacting bones and soft tissues that often display a distinctive genetic background characterised by minimal mutations and genetic stability. Around 40% of sarcomas arise from a single chromosomal translocation, resulting in a fusion protein often involving chromatin regulators, which serves as an oncogenic driver. These fusions form chimeric transcription factors that alter gene expression, disrupting critical pathways that govern cell growth, differentiation, and survival. Despite having a clear driver, there has been little progress in translating genomic discoveries towards understanding the biology of distinct genotypes in sarcomas and developing biology-informed diagnostic tools or treatments.

In this project, we will investigate the impact of oncogenic fusions on chromatin and gene regulation to unravel if they form distinct sarcoma sub-types, what markers can be used for their classification to improve diagnostic precision and how this can guide the development of targeted therapeutic approaches?

By introducing oncogenic fusions into isogenic backgrounds we will analyse their molecular signatures through exploration of their influence on gene expression (RNA sequencing), chromatin structure (ATAC-seq), and genomic profile (CUT&RUN). We will then integrate this data using the computational gene regulatory networks (GRaNIE) and transcription factor activity (diffTF) pipelines to investigate the direct impact of these chimeric transcription factors on their target genes. Furthermore, we seek to reveal what additional critical transcription factors they activate and their role in driving cellular transformation.

This project establishes three main aims: 1) classify oncogenic fusions by their unique molecular signatures to identify new sarcoma subgroups, 2) discover biomarkers for quicker, more precise sarcoma diagnosis, and 3) develop targeted treatment strategies for these subgroups. Our goal is to advance sarcoma classification and understanding by identifying shared oncogenic processes, thereby improving current diagnosis tools and enabling the development of targeted treatments. 

Who should apply?

We are seeking motivated students excited by new opportunities who are keen to engage in high quality biomedical research. Applicants should have a UK or international 1st class or 2.1 degree or a Masters in any relevant discipline in biological or biomedical sciences. Applications are open to all individuals irrespective of nationality or country of residence. All applicants should satisfy the University of Edinburgh’s English language requirements. 

Studentships are available to start in September 2024. These studentships are fully funded and include tuition fees, an allowance for research consumables and an enhanced UKRI stipend of £20,122 p/a.

Application procedure

Closing date: 19 May 2024.

Interviews: 12-13 June 2024.

To apply for this PhD studentship, please go to our Graduate Research and Training website (www.ed.ac.uk/mrc-human-genetics-unit/graduate-research-and-training).

For informal enquiries about this project, please contact Nezha Benabdallah ([email protected]).

For more information about the research that we do, please visit our websites (www.ed.ac.uk/mrc-human-genetics-unit and http://www.mdc-berlin.de).