金属配合物导致基因组化学修饰的测序技术开发和分布规律解析

本申请对应指南中“针对金属及其配合物导致的DNA、组蛋白等生物大分子的化学修饰，发展探测其动态特征、揭示其分布规律的新技术、新方法”这一研究重点。包含顺铂在内的金属药物是当今使用最广的癌症治疗药物。铂类配合物靶向DNA上GG、AG等二聚核苷酸，然而其全基因组范围内的作用位点研究尚少。此外，金属配合物结合DNA后，如何导致基因组（DNA和组蛋白等）中内源表观遗传修饰的变化，也知之甚少。本项目拟在我们以往工作的基础上，针对代表性的铂类配合物，发展检测其结合基因组DNA位点的测序新技术，解析其分布规律；同时，通过化学标记等交叉学科手段，开发在单细胞、单分子水平上检测基因组内源化学修饰的新方法，研究在铂类药物处理过程中表观遗传图谱的动态特征。这些测序新技术的开发及修饰位点分布规律的解析，有助于阐明铂类药物的作用机制和产生耐药性的分子机制，为新型金属抗肿瘤药物的设计提供理论基础。

This proposal aims at “Development of novel technologies to detect and profile metal and its complexes induced chemical modifications to biomacromolecules (DNA, histone and etc.)” in the application guideline. Metal complexes, including cisplatin, are the widely used anti-cancer drug in the world. Cisplatin and other metal complexes target the GG and AG dinucleotide in DNA; however, the genome-wide distribution of their target sites is poorly studied. In addition, how endogenous epigenetic modifications in the genome (DNA, histone and etc.) are altered upon metal complex binding is also unknown. Based on our previous work, this application aims to develop new sequencing methods to detect the binding sites of representative metal complexes and to elucidate its distribution pattern; meanwhile, by chemical labeling and other interdisciplinary means, we aim to develop sequencing technologies for endogenous epigenetic modifications at the single-cell and single-molecule level, so as to understand their dynamics upon drug treatment. Such new tools and the elucidation of the distribution patterns of these chemical modifications will lead to better understanding to the mechanism of metal complexes and drug resistance, thereby contributing to better design of anti-tumor metal drugs in the future.