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Unravelling epigenetic drivers of chemo-resistance by optical editing of DNA-methylation in cells.

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  • Full or part time
    Dr M Di Antonio
    Prof R Brown
    Dr Lorenzo Di Michele
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

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.

Funding Notes

Funded by the CDT in Chemical Biology: Innovation in Life Sciences -

Related Subjects

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FTE Category A staff submitted: 54.90

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