N6-甲基腺苷结合蛋白YTHDF2相分离在砷诱导氧化应激中的作用和机制

砷的健康危害是严重的公共卫生问题，表观遗传学的发展为砷毒性机制研究提供了新思路。研究显示RNA表观遗传修饰N6-甲基腺苷（m6A）参与调控砷诱导的氧化应激，但m6A精确调控砷诱导氧化应激的机制还远不清楚。最新研究发现：应激条件下多价m6A修饰驱动结合蛋白YTHDF2相分离，发生相分离的分子共同定位至应激颗粒，为探究细胞应激的精细调控带来了新见解。目前，人们仅探究了m6A驱动YTHDF2相分离的条件，而YTHDF2相分离的功能研究尚属空白。本项目以砷诱导氧化应激为切入点，首次研究m6A驱动的YTHDF2相分离在砷诱导氧化应激中的作用及机制，从相分离视角重新审视RNA表观遗传修饰m6A在砷诱导细胞氧化应激中的精细调控过程，揭示YTHDF2相分离在砷致氧化应激的生物学意义，并有望发现全新的氧化应激生物标志物。本研究的立项依据和学术思想来源于权威学术期刊最新线索，具有明显的创新性和重要的学术价值。

The health hazard of arsenic has become a serious public health problem and oxidative stress has been recognized as the main basis of arsenic toxicity. However, the precise regulation of oxidative stress induced by arsenic is not clear in the levels of epigenetics and subcellular components. The development of RNA epigenetics and the phase separation of biological macromolecules shed light on the new mechanisms of arsenic toxicity. It has been reported that N6-methyladenosine (m6A), the most abundant and reversible RNA posttranscriptional modifications, was involved in arsenite-induced oxidative stress. However, the detailed modulations of m6A-mediated oxidative stress induced by arsenite remain poorly understood. Recent studies showed that multivalent m6A-methylated RNAs promote phase separation of m6A binding protein YTHDF2 under stress states, and the molecules that undergoing the phase separation localize in stress granule altogether, opening a new avenue for the precise mechanisms of cell stress. So far, the studies of YTHDF2 phase mainly focus on the conditions of m6A-dependent YTHDF2 phase separation. However, there is no study showing the biological functions of YTHDF2 phase separation, particularly in the aspect of oxidative stress induced by arsenic. In this project, we propose to explore the functions and mechanisms of m6A-driven YTHDF2 phase separation in arsenite-induced oxidative stress. Our study will provide the first evidence that RNA epigenetic m6A modification-mediated phase separation plays a pivotal role in oxidative stress induced by arsenic. Also, the results will elucidate the biological significances of YTHDF2 phase separation in arsenite-induced oxidative stress, and find a novel biomarker of oxidative stress. The scientific ideas on the proposal come from the latest clues of the high impact journals, so our proposal is of great scientific value and highly innovative.