砷是确认的人类致癌物，地方性砷中毒致病致癌机制至今不明是其未得以彻底控制的瓶颈问题，也是各国政府和学者高度关注的重大公共卫生问题。砷影响DNA损伤修复是砷致癌的始动因素已被众多学者认可，但机制尚不明确；新近研究推测，组蛋白修饰在DNA损伤修复过程及诱导疾病结局中起重要作用。本项目在课题组前期研究基础上，以贵州省燃煤污染型砷暴露人群为研究对象，采用荧光定量PCR、免疫沉淀、免疫印迹、定量质谱等方法探索砷暴露人群组蛋白修饰特征，分析其与DNA损伤修复的关系；采用基因重组方法构建细胞DNA双链断裂（DSB）模型，并应用该模型筛选砷特异性组蛋白修饰；采用组蛋白修饰特异位点突变技术或RNA干扰敲除组蛋白修饰酶技术，探索组蛋白修饰在砷致DSB损伤修复中的调控机制，从人群和体外实验两个体系、侧重组蛋白修饰调控新角度揭示砷的致病致癌机制，同时为寻找可能用于砷中毒防治的组蛋白修饰标志物性提供新思路和依据

Arsenic is a confirmed human carcinogen. The arsenic pathogenic and carcinogenic mechanism is still unknown, which become the bottleneck problem for the complete control of endemic arsenism. As well as the major public health problem that is concerned by governments and scholars. Inhibition of DNA damage and repair has been recognized as the initial cause for arsenic carcinogenic function by many scholars, but the mechanism is not clear. Recent study showed that histone modifications play an important role in DNA damage repair process and in diseases development. In our study, based on the results of early stage research, the population exposed to endemic arsenic pollution from coal-burning in Guizhou province was selected as the research object, using real-time fluorescence quantitative polymerase chain reaction PCR(FQ-PCR), immunoprecipitation, western blotting, quantitative mass spectrometry to explore the characteristics of histone modifications in them, and to analyze the relationship between histone modifications and DNA damage and repair. Meanwhile, we build cell DNA double-strand breaks (DSB) model with gene recombination technology, and select the special histone modifications of arsenic with the cell model. And using the technology of point mutations in histone modifications or RNA interference knockout histone modification enzyme, to explore the histone modifications in the regulatory mechanism of DSB damage and repair caused by arsenic. The arsenic pathogenic and carcinogenic mechanism will be explored from new angle--histone modifications regulation in vivo and in vitro experiments system. And finding histone modifications biologic markers to provide a new ideas and new evidences for the prevention and therapy of arsenism.