Unravelling epigenetic drivers of chemo-resistance by optical editing of DNA-methylation in cells.
Dr M Di Antonio
Prof R Brown
Dr Lorenzo Di Michele
No more applications being accepted
Funded PhD Project (European/UK Students Only)
Aberrant DNA-methylation is a well-established driver of acquired resistance in ovarian cancer, although such epigenomic changes occur within a high background of passenger events and current epigenetic chemical biology tools generally affect the entire epigenome rather than locus specific.
This makes it challenging with current biological tools to investigate the role of key locus specific methylation events in resistance mechanisms. To overcome this, epigenetic editing using CRISPR-Cas9 fused to epigenetic modifiers is increasingly being evaluated, although current approaches have the limitation of not being inducible. To identify key drivers of resistance and demonstrate phenotypic effects, we aim to generate novel chemical ligands that enable light-controlled positioning of DNA-methylation writer and eraser (e.g. DNMTs and TETs) at specific genomic loci by means of CRISPR-Cas9.
These chemical tools will disentangle the role of site-specific methylation in patient-derived cell-lines and xenografts. The light-controlled positioning of the epigenetic modifiers will enable temporal control of epigenetic modification, allowing evolution of resistance and its prevention or re-sensitisation to be studied in a time-dependent manner that is essential to study dynamic epigenetic-based processes such as acquired resistance to chemotherapy.
Funded by the CDT in Chemical Biology: Innovation in Life Sciences - https://www.imperial.ac.uk/chemical-biology/cdt/.
How good is research at Imperial College London in Chemistry?
FTE Category A staff submitted: 54.90
Research output data provided by the Research Excellence Framework (REF)
Click here to see the results for all UK universities