宫颈癌新的表观遗传学特征鉴定及其调控机制研究

宫颈癌是严重威胁女性健康的恶性肿瘤，高危型HPV感染是其发生根本，但仅少数持续感染者进展为宫颈癌，表明存在其他关键决定因素。m6A和m5C形式的RNA甲基化是新的表观遗传学修饰手段，我们发现m6A去甲基化酶FTO在宫颈高级别病变组织显著高表达；多个与宫颈癌发生密切相关基因存在m5C修饰，且受m5C甲基转移酶NSUN2调控，表明RNA甲基化修饰在肿瘤发生过程中起重要调控作用。为阐明m6A和m5C在宫颈癌演进过程作用机制，拟开展1）综合基于m6A抗体富集以及RNAm5C重压硫酸盐高通量测序，在宫颈癌、癌前病变和正常组织中绘制精细转录组修饰图谱，揭示其分布特征及规律; 2）结合转录组大数据，鉴定RNA甲基化介导调控的关键靶基因并揭示其具体机制; 3）整合转录及表观转录组数据，挖掘RNA修饰间Crosstalk; 4）证实关键结合蛋白在宫颈癌演进过程的规律，设计制定新的临床筛查策略。

Cervical cancer is a malignant carcinoma that seriously threatens the women’s health. High-risk HPV infection is recognized as the main cause of cervical cancer. However, there are only a few people with persistent HPV infection to progress to cervical cancer, indicating that the exact mechanisms of cervical cancer have still reminded unknow. The recently discovery of reversible RNA methylation has opened a new realm of epigenetics. N6-methyladenosine (m6A) and 5-methylcytosine (m5C) represent the most prevalent internal modification in mammalian RNAs. We found that FTO as a m6A demethylase was significantly increased in the tissues of cervical high-grade squamous intraepithelial lesion, compared to normal control. Meanwhile, we observed that many sites of m5C modification have located in the genes, which are closely correlated to cervical cancer. And these genes are regulated by m5C RNA methyltransferase NSUN2. These results indicated that RNA methylation modifications play important regulatory role during tumorigenesis of cervical cancer. In order to illuminate the specific role of RNA epigenetic modifications in the evolution process of cervical cancer, we will perform: 1) By using the method of MeRIP-seq, miCLIP-seq and RNA-BisSeq, we will profile the transcriptomic landscape of modifications during the evolution process of cervical cancer to reveal the dynamic characteristics in different tumorigenesis stages; 2) Combined with high-throughput RNA sequencing, we want to identify the RNA methylation-mediated target transcripts and reveal its regulatory mechanism; 3) Integrated the data of both transcriptome and epitranscriptome, we will build the crosstalk network among RNA modifications; 4) As the specific RNA methylation-mediated gene validated, we plan to design the new strategies of clinical screening for cervical cancer.