Functional genomics and development of clinical genome editing strategies

The Davies laboratory aims to understand how the genome is read by the cells of the blood and bone marrow
and how the sequence can be edited to treat human disease. This is important because genetic variation in bloodcells alters the susceptibility to many different human diseases including infection, autoimmune disease and
malignancy. Genome editing of these cells has the potential to cure many diseases but this technology can only be safely used if we understand the effects of altering the genome sequence.

Over 90% of all DNA sequences that are associated with human disease alter how genes are controlled rather
than in the protein produced by the gene. The laboratory has world class expertise in developing new techniques
for determining the physical structure of DNA within cells, which is key to understanding how the genome
functions. We will use this technology to investigate the fundamental principles that control genes. We will also
use it to map the key DNA sequences that control genes in important blood and bone marrow cell types.

We aim to translate this by developing new and safer ways of editing the genome of bone marrow stem cells
which can be transplanted to treat human disease.

The Davies laboratory focuses on understanding gene regulation through combining genomics, bioinformatics and genome editing approaches. We also have a major interest in translating this expertise to develop clinical genome editing strategies for treating human disease in the context of haemopoietic stem cell transplantation.

Many genes are controlled by regulatory elements called promoters that lie adjacent to the transcription start site and enhancers that are located 104-106 base pairs distant from the gene. The laboratory have developed an innovative technique called Micro Capture-C (MCC), which makes it possible to define physical contacts at base pair resolution when previous methods have limited resolution below 500 base pairs. We will explore the fundamental mechanisms controlling gene regulation by improving this approach and combining it with other functional genomics approaches. This will include the use of degrons to remove key components of the transcriptional machinery. Through extensive collaboration within the MHU we wish to map the chromatin landscape to understand how variants in enhancers cause abnormal haemopoiesis. We will also engineer cellular models to test the function of perturbing regulatory elements at scale including the use of CRISPR screens.

Having previously developed clinical approaches for treating haemoglobinopathies using base editing; we plan to go on to develop a method of editing haemopoietic stem cells to improve the safety of transplantation through inducing a druggable selective advantage. In addition, we are using our expertise in functional genomics to assess the safety of genome editing approaches, in which the majority of off-target mutations occur in the non-coding genome.