Human Genetics, Genomics and Disease: Understanding how nuclear architecture affects neuronal function in health and disease

Location:     MRC Human Genetics Unit, University of Edinburgh, UK & Max Delbrück Center Berlin Institute for Medical Systems Biology, Berlin, Germany   

Supervisors: Prof Nick Gilbert, Dr Marina Chekulaeva

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 Berlin Institute for Medical Systems Biology (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

Information in the form of DNA is transcribed into RNA, processed in the nucleus and exported to the cytoplasm where it is translated to make proteins. Individual parts of this pathway are well understood but it is not clear how they function together in normal develop, or why mutations in proteins give rise to developmental phenotypes in specific tissues. Over the last 10-years we have been studying a protein called SAF-A (Scaffold attachment factor A; also called HNRNPU). We have shown this is an abundant ubiquitously expressed protein that is important for forming interconnected microgels in the cell nucleus, which provide a unique environment for regulating chromatin (DNA/histone proteins) folding and gene expression. Surprising recent data, obtained from deep sequencing individuals with developmental delay, intellectual disability and autism, show that some patients have missense or loss of function mutations in SAF-A.

In this study we will investigate how SAF-A, a protein important for nuclear biology, can give rise to a neurological defect. Our hypothesis is that SAF-A forms a nuclear environment that can facilitate mRNA transport outside the nucleus and target it for translation. We have laid the groundwork for the project by developing a protocol for the efficient generation of motor neurons from hiPSCs. We have also developed a method to isolate neuronal subcellular compartments – cell bodies and axons – for omics analysis, including proteomic, RNA-seq, SLAM-seq, and Ribo-seq (often called spatial omics). Additionally, we developed a technique to map RNA localization elements by integrating a massively parallel reporter assay with the isolation of neuronal compartments, called N-zip (neuronal zipcode identification protocol).

Building on this foundation we will apply spatial omics to hiPSC-derived motor neurons depleted of SAF-A or with mutations in individual SAF-A domains. This will enable us to identify proteins and RNAs with varying localization, stability, and translation across the subcellular compartments of SAF-A depleted or mutated neurons, and to identify the regulatory and molecular mechanisms underlying SAF-A related neuronal disease.

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 Nick Gilbert ([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).