Mapping and Editing Gene Regulatory Networks to Develop Therapies for Genetic Disorders.

About the project

About the Project Inherited diseases are often caused by mutations within genes, but an increasing number arise from variants in the regulatory elements that control when and where genes are switched on. Understanding these regulatory mechanisms remains a major challenge in human genetics. This DPhil project aims to uncover new mechanisms underlying inherited disease by systematically mapping regulatory elements across haematological and neurological tissues. The project will use Micro Capture-C, a technique developed in our laboratory that maps the three-dimensional structure of DNA within chromatin at unprecedented resolution (Hua et al., Nature 2021; Li et al., Cell 2025; Hamley et al., Nature Genetics, in press). Micro Capture-C enables interactions between cis-regulatory elements and hundreds to thousands of gene promoters to be mapped simultaneously, providing a powerful approach for linking disease-associated variants to the genes and pathways they disrupt. Candidate regulatory elements and disease mechanisms identified through these maps will then be tested at scale using high-throughput CRISPR screening and functional genomic approaches. By combining cutting-edge mapping of chromatin architecture with genome engineering, the project will identify previously unrecognised mechanisms of inherited disease. Editing of regulatory sequences has been used to upregulate fetal haemoglobin for the treatment of sickle cell disease and thalassaemia, a strategy that was developed through an in depth understanding of the beta globin locus. We plan to map the regulatory landscape of over 1800 genes associated with neurodevelopmental disorders which will establish a foundation for developing advanced genome-editing strategies to correct pathogenic mutations. Project Objectives Mapping the cis-regulatory landscape of genes associated with inherited diseases Developing CRISPR screens to test these at scale Identification of cases in Genomics England Datasets Confirmation of changes Research Methodologies The research methodologies will include Micro Capture-C and other functional genomics assays including ChIP, ATAC-seq and RNA-seq. The student will develop bioinformatic skills to analyse these data types Potential Project Impact The project has the potential to enable unsolved cases of genetic disease to be diagnosed It has the potential to identify new mechanisms that cause disease Proposed Project Timelines Data generation with Micro Capture-C – years 1-3 Analysis of data – years 1-4 CRISPR screens – years 2-4 Write up of publications and thesis – year 4 Potential Internship/Exceptional Training Opportunities Training opportunities include: Molecular techniques including ATAC-seq, ChIP-seq and RNA-seq Chromosome conformation capture – Micro Capture-C High throughput CRISPR screens (cloning, cell culture, analysis, possibly single cell technologies) Bioinformatics analysis of functional genomics data Working with the GEL environment Opportunities for student participation in PPIE There will be excellent opportunities for the student to participate in PPIE through the MRC CoRE and wider research group. Both main supervisors are clinically active, providing strong links with patients and families affected by inherited disorders. The student will have opportunities to engage with patient groups, communicate research findings, and contribute to wider public engagement activities. MRC CoRE-TG Scholarships Applicants to MRC CoRE-TG projects may be nominated for a CoRE-TG DPhil scholarship, which involves a second interview following the departmental interview. Due to UKRI limits on international student recruitment, only UK home students are eligible for these MRC CoRE-TG DPhil scholarships. For information on home student eligibility, please refer to UKRI training grants: standard terms and conditions of training grant sections TGC 5.2.4 & TGC 5.2.5. The MRC CoRE-TG DPhil scholarship provides funding for: Course fees for the duration of fee liability. A living stipend at the UKRI rate, paid for four years. A £20,000 Research Training Support Grant (RTSG) to support research and training costs. A £1,200 travel allowance to support research-related travel and development opportunities. The stipend rate is reviewed annually by UKRI/MRC. Overseas applicants are still welcome to apply for MRC CoRE-TG projects. They may be considered for other funding opportunities available through the relevant department and may also apply for external scholarship funding independently to support their DPhil. Ready to join us? Applications are competitive and will be assessed according to the admissions requirements of the relevant host department or university. For questions about the MRC CoRE in Therapeutic Genomics programme , please contact mrccoretg@paediatrics.ox.ac.uk . Scholarship Code: CoRE-TG 2026-006

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