LncRNA及其表观遗传学调控在人类肿瘤发生发展中发挥重要调节功能。通过LncRNA启动子甲基化芯片以及LncRNA表达谱芯片的联合分析，筛选出了同时发生异常甲基化和异常表达的LncRNA，并选取BRE-AS1进一步研究。其在肾癌中显著低表达且受启动子甲基化调控。体内外实验证实了其在肾癌中起肿瘤抑制作用。随后CLIP数据及RNA免疫沉淀，验证出其与HNRNPU结合，且HNRNPU与GADD45A存在表达及功能相关。因此提出假说，BRE-AS1在肾透明细胞癌中高甲基化表达，其能够通过RNA结合蛋白HNRNPU的桥接作用，调控GADD45A的表达，而GADD45A又能够影响碱基断裂修复相关的启动子去甲基化过程，导致下游基因如BABAM2表达异常，从而调控肾癌的发生发展。本项目拟阐明BRE-AS1通过HNRNPU调节GADD45A相关通路在肾癌发生发展中的分子机制，加深对肾癌相关分子事件的认识。

Long noncoding RNAs (lncRNAs) have been documented as playing critical role in the development and progression of human cancers including renal cell carcinoma (RCC), while the epigenetic regulation of lncRNAs are also widely studied. Our integrated analysis of lncRNA promoter methylation sequencing and lncRNA expression profile analysis identified a series of lncRNA with both aberrant expression and abnormal promoter methylation status in RCC. In order to validate our results, we selected a novel lncRNA BRE-AS1 which was significantly downregulated in ccRCC and exhibited hypermethylation status in promoter region. The expression pattern and methylation regulation were proved with further studies, and a series of in vitro and in vivo experiments validated that BRE-AS1 could act as an tumor suppressive transcript. Furthermore, crosslinking-immunprecipitation and high-throughputsequencing (CLIP-seq) data and our subsequent RNA immunoprecipitation identified HNRNPU as a RNA binding protein of BRE-AS1, and there was a significant expression and functional correlation between HNRNPU and GADD45A. All these results contributed to the hypothesis that methylation-silenced BRE-AS1 might regulate the GADD45A expression and base break repair associated promoter demethylation pathway through its RNA binding protein HNRNPU, thus participating in the carcinogenesis of RCC. This project aims to elaborate the molecular mechanisms that how BRE-AS1 affects the pivotal GADD45A-associated promoter demethylation pathway in RCC via interaction of HNRNPU and GADD45A. This project has the potential to broaden and deepen our understanding of RCC-associated molecular events and provides promising diagnostic and therapeutic targets for RCC.