: Identification of essential genes in the innate epigenetic response to environmental agents that underpins resistance to therapeutic drugs

Histone deacetylase inhibitors (HDACi) such as short-chain fatty acids and hydroxamic acid derivatives, are bacterial products and widespread environmental and dietary components. A coordinated transcriptional response involving up- and down-regulation of selected genes, allows eukaryotic cells to survive the potentially toxic epigenetic disruption caused by these agents. Through knockdown and CRISPR in cell lines, the project explores the signalling pathways through which this response is initiated and sustained and aims to identify key components. Specifically, it asks how HDACi-induced acetylation can trigger changes in DNA methylation. Using a panel of Burkitt Lymphoma cell lines sensitive and resistant to HDACi, it tests the hypothesis that inactivation, through mutation, of components of the resistance pathway explains why individual cancers can be so sensitive to HDACi, whilst most are resistant.