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

组蛋白去乙酰化酶抑制剂（HDACi），如短链脂肪酸和羟肟酸衍生物，是细菌产物和广泛的环境和饮食成分。一种协调的转录反应涉及选定基因的上调和下调，使真核细胞能够在这些药物引起的潜在毒性表观遗传破坏中存活下来。通过在细胞系中敲低和CRISPR，该项目探索了这种反应启动和持续的信号通路，旨在确定关键成分。具体来说，它询问了hdaci诱导的乙酰化如何触发DNA甲基化的变化。利用一组对HDACi敏感和耐药的伯基特淋巴瘤细胞系，它检验了一种假设，即通过突变使耐药途径的成分失活，解释了为什么个别癌症对HDACi如此敏感，而大多数癌症对HDACi具有耐药性。

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.