乳腺癌中p53调控增强子的特征与功能分析  

Characteristics and Functional Analysis of p53-regulated Enhancers in Breast Cancer

作　　者：张茵 王文著 谭政堂 李昶蓥 岳俊杰 郭志云[1] ZHANG Yin;WANG Wen-zhu;TAN Zheng-tang;LI Chang-ying;YUE Jun-jie;GUO Zhi-yun(School of Life Science and Engineering,Southwest Jiaotong University,Chengdu 610031,Sichuan,China;Institute of Biotechnology,Academy of Military Medical Sciences,PLA Academy of Military Science,Beijing 100071,China)

机构地区：[1]西南交通大学生命科学与工程学院,中国四川成都610031 [2]中国人民解放军军事科学院军事医学研究院生物工程研究所,中国北京100071

出　　处：《生命科学研究》2020年第6期476-483,共8页Life Science Research

基　　金：传染病防治科技重大专项(2018ZX10101-003-001-008)。

摘　　要：先前研究表明p53可参与增强子调控并影响染色体可及性。然而,在乳腺癌中结合p53的增强子特征以及p53与增强子形成的调控网络尚不清楚。为此,通过整合多组学数据,共识别MCF-7细胞中459个p53调控的增强子(Enhp53)。通过比较发现,Enhp53的表达量以及组蛋白修饰信号H3K4me1、H3K4me2、H3K4me3、H3K9ac、H3K27ac均显著高于未结合p53的增强子(Enhno-p53)。通过分析76种转录因子的ChIP-seq数据,共发现了36个与p53协同调控增强子的转录因子,如GATA3、FOXA1以及DPF2。通过分析MCF-7细胞在Nutlin处理前后的RNA-seq数据,在近端调控和远端调控两个层面上共识别了148对Enhp53-mRNAs,其中FOS基因受两个增强子调控并显著影响乳腺癌患者的总生存时间。功能富集分析发现,Enhp53靶基因在DNA损伤、细胞凋亡以及p53介导的肿瘤信号通路中显著富集。上述结果表明Enhp53与Enhno-p53的特征具有显著差异,且p53通过协同其他转录因子共同结合在Enhp53上从而参与乳腺癌的生物进程与信号通路。Previous studies have shown that p53 can participate in enhancer regulation and affect chromosome accessibility.However,the feature of p53-regulated enhancers as well as the regulatory network formed by p53 and enhancers in breast cancer are unclear.To this end,multiple omics data were integrated and 459 p53-bound enhancers(Enhp53)were identified in MCF-7 cells.By comparison of their characteristics,it was found that Enhp53 expression and H3K4me1,H3K4me2,H3K4me3,H3K9ac,and H3K27ac signals were sig nificantly higher than those of p53-unbound enhancers(Enhno-p53).By analyzing the ChIP-seq data of 76 transcription factors,36 transcription factors,such as GATA3,FOXA1,and DPF2,were found to co-regulate enhancers with p53.By analyzing the RNA-seq data before and after activation by Nutlin in MCF-7 cells,a total of 148 Enhp53-mRNAs were identified at both proximal and distal regulatory levels,among which FOS was regulated by two enhancers and affected the overall survival time of breast cancer patients significantly.Functional enrichment analysis found that Enhp53 target genes were enriched in DNA damage,apoptosis,and p53-mediated tumor signaling pathways significantly.The above results indicate that Enhp53 is different from Enhno-p53,and p53 binds to Enhp53 by cooperating with other transcription factors and then participates in biological processes and signaling pathways in breast cancer.

关 键 词：P53 增强子 乳腺癌 转录因子 

分 类 号：Q523.1[生物学—生物化学] R737.9[医药卫生—肿瘤]