增强子及相关调控组在肠型胃癌中的重塑特征及其预后预测模型  

Remodeling characteristics and construction of a survival prediction model based on enhancers and regulome in intestinal type gastric cancer

作　　者：陈旭 储召乐 秦苾珺 刘碧颖 李先锋 王涛 刘文康 王斌 CHEN Xu;CHU Zhaole;QIN Bijun;LIU Biying;LI Xianfeng;WANG Tao;LIU Wenkang;WANG Bin(Medical College of Chongqing University,Chongqing,400044;Department of Gastroenterology,Chongqing Key Laboratory of Precise Prevention and Treatment of Digestive Malignancies,Army Medical Center of PLA,Chongqing,400042,China)

机构地区：[1]重庆大学医学院,重庆400044 [2]陆军特色医学中心消化内科,消化系统肿瘤精准防治重庆市重点实验室,重庆400042

出　　处：《陆军军医大学学报》2024年第7期695-704,共10页Journal of Army Medical University

基　　金：国家自然科学基金优秀青年科学基金(81822032);重庆市杰出青年基金(cstc2019jcyjjqx0027)。

摘　　要：目的研究组蛋白H3K27ac修饰在肠型胃癌的全基因组分布情况,探讨其增强子及相关调控组重塑特征,建立临床预后评估模型。方法收集于2022年1-12月在我院消化内科就诊患者的15例肠型胃癌组织与18例正常胃黏膜组织进行靶向H3K27ac修饰的染色质靶向捕获(cleavage under targets and tagmentation,CUT&Tag)测序,采用生物信息学分析,比较两种组织H3K27ac修饰在基因组的分布差异;基于H3K27ac修饰分布特征,鉴定增强子元件,探讨增强子及相关调控组的重塑特征;采用单因素Cox和多因素Cox等回归分析方法,构建增强子相关靶基因的预后预测模型。结果两种组织的H3K27ac修饰的基因组分布特征无明显差异,主要位于增强子区域;与正常胃黏膜相比,肠型胃癌增强子H3K27ac修饰的整体水平更高;共鉴定出8847个在肠型胃癌中活性增加的增强子(获得性增强子),占所有增强子的8.3%,其可能促进胃癌细胞增殖、黏附等恶性行为;联合6个获得性增强子相关靶基因(BHLHE41、CEP97、CHI3L2、NR6A1、SUPT3H和TOMM20)构建的预测模型,能够较好地推测患者总体生存期。结论增强子重塑是肠型胃癌显著的表观遗传学特征之一,增强子可能通过上调MYC、E2F3等基因表达促进癌细胞恶性增殖与黏附行为,并基于增强子靶基因构建预后模型。Objective To explore the genome-wide distribution of histone H3K27ac in intestinal type gastric cancer,analyze remodeling features of enhancers and regulome and construct a prediction model for prognosis.Methods H3K27ac CUT&Tag sequencing and RNA sequencing were performed in intestinal type gastric cancer tissues from 15 patients and normal gastric mucosa tissues from 18 healthy volunteers.Bioinformatics analysis was performed to identify the differences in genome distribution of H3K27ac modifications.Based on the distribution characteristics of H3K27ac,the enhancer elements were identified and the remodeling characteristics of enhancer and related regulome were explored.The prediction model for prognosis based on enhancer related target genes was constructed by univariate Cox and multivariate Cox regression analyses.Results The histone H3K27ac modification was mainly distributed in the enhancer region and displayed no significant differences in the genomic distribution patterns between normal and cancer tissues.Compared with normal gastric mucosa,the level of enhancer H3K27ac modification was higher in intestinal type gastric cancer.A total of 8847 enhancers with increased activity in intestinal type gastric cancer were identified,accounting for 8.3%of all enhancers,which might promote malignant behaviors such as proliferation and adhesion of gastric cancer cells.A prognosis-predicting model established based on a panel of 6 genes that upregulated by the acquired enhancer in cancers,which was able to predict the overall survival of patients.Conclusion Enhancer remodeling is one of the significant epigenetic features of intestinal type gastric cancer.These enhancers may drive malignant growth and adhesion of cancer cells by upregulating the expression of MYC,E2F3 and other genes.A prognosis model based on enhancer target genes is constructed.

关 键 词：肠型胃癌 表观基因组学 H3K27ac 增强子 预后 

分 类 号：R318.04[医药卫生—生物医学工程] R394.3[医药卫生—基础医学] R735.2