: 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）如短链脂肪酸和异羟肟酸衍生物是细菌产物和广泛的环境和饮食成分。涉及上调和下调选定基因的协调转录反应允许真核细胞在由这些试剂引起的潜在毒性表观遗传破坏中存活。通过细胞系中的敲除和CRISPR，该项目探索了启动和维持这种反应的信号通路，并旨在确定关键成分。具体来说，它询问HDACi诱导的乙酰化如何引发DNA甲基化的变化。使用一组对HDACi敏感和耐药的伯基特淋巴瘤细胞系，它测试了这样一种假设，即通过突变，耐药途径组分的失活解释了为什么个体癌症对HDACi如此敏感，而大多数癌症都具有耐药性。

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.