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

通过细胞中 DNA 甲基化的光学编辑揭示化疗耐药性的表观遗传驱动因素

基本信息

批准号：
2635818
负责人：
金额：
--
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2635818
关键词：
Unravelling epigenetic drivers chemo resistance

项目摘要

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 CRISPRCas9 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 CRISPRCas9. 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 resensitisation to be studied in a time-dependent manner that is essential to study dynamic epigenetic based processes such as acquired resistance to chemotherapy.

异常DNA甲基化是卵巢癌获得性耐药性的公认驱动因素，尽管此类表观基因组变化发生在乘客事件的高背景下，并且当前的表观遗传化学生物学工具通常影响整个表观基因组，而不是位点特异性。这使得利用当前的生物学工具来研究关键基因座特异性甲基化事件在抗性机制中的作用具有挑战性。为了克服这一点，使用CRISPRCas9融合到表观遗传修饰剂的表观遗传编辑越来越多地被评估，尽管目前的方法具有不可诱导的局限性。为了鉴定抗性的关键驱动因素并证明表型效应，我们的目标是产生新型化学配体，其能够通过CRISPRCas9在特定基因组位点处光控定位DNA甲基化写入器和擦除器（例如DNMT和TMT）。这些化学工具将解开位点特异性甲基化在患者来源的细胞系和异种移植物中的作用。表观遗传修饰剂的光控定位将使得能够对表观遗传修饰进行时间控制，从而允许以时间依赖性方式研究抗性的演变及其预防或再致敏，这对于研究基于动态表观遗传的过程（例如对化疗的获得性抗性）是必不可少的。