组蛋白H3K27me3沉默子重塑上调胃黏膜高级别上皮内瘤变磷酸甘油醛激酶1表达  

Remodeling of histone H3K27me3-associated silencers upregulates PGK1 expression in gastric high-grade intraepithelial neoplasia

作　　者：秦苾珺 谭玉婷 储召乐 刘碧颖 李先锋 王涛 陈东风 崔红娟[1] 吴林育 王斌 QIN Bijun;TAN Yuting;CHU Zhaole;LIU Biying;LI Xianfeng;WANG Tao;CHEN Dongfeng;CUI Hongjuan;WU Linyu;WANG Bin(Southwest University Medical Research Institute,Chongqing,400715;Department of Gastroenterology,Chongqing Key Laboratory of Precision Diagnosis and Treatment for Digestive Malignancies,Army Medical Center of PLA(Daping Hospital),Army Medical University(Third Military Medical University),Chongqing,400042;School of Medicine,Chongqing University,Chongqing,400044,China)

机构地区：[1]西南大学医学研究院,重庆400715 [2]陆军军医大学陆军特色医学中心(大坪医院)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 [3]重庆大学医学院,重庆400044

出　　处：《陆军军医大学学报》2024年第6期597-607,共11页Journal of Army Medical University

基　　金：国家自然科学基金资助项目(81822032,91959111,81872027);重庆市自然科学基金项目(cstc2019jcyjjqX0027,cstc2021jcyj-msxmX0340)。

摘　　要：目的 绘制胃黏膜高级别上皮内瘤变(High-Grade Intraepithelial Neoplasia, HGIN)组织的组蛋白H3K27me3沉默子图谱,寻找沉默子调控的重要靶基因。方法 从本院内镜中心收集HGIN与正常胃黏膜组织各24例,采用H3K27me3染色体靶向切割和标签化(Cleavage Under Target&Tagmentation, CUT&Tag)测序技术捕获基因组修饰区域。通过生物信息学分析比较两类组织的沉默子信号特征以及差异;整合RNA测序数据及高通量染色体构象捕获技术(Hi-C)公共数据,分析沉默子重塑调控的靶基因及调控的潜在生物学过程。结果 与正常胃黏膜相比,HGIN组织H3K27me3修饰数量减少,信号强度全局性降低,呈现H3K27me3信号峰重塑现象;转录组差异分析结果显示,与正常胃黏膜组织相比,HGIN共有8 887个差异表达基因,其中表达上调基因4 335个,表达下调基因4 552个,其中CTNNB1等肿瘤发生相关基因显著上调;整合分析表观组学和转录组学数据,发现沉默子丢失可能在转录水平上调氨基酸生物合成、精氨酸与脯氨酸代谢和糖酵解等关键代谢基因,如糖酵解关键酶磷酸甘油醛激酶1(phosphoglycerate kinase1,PGK1)表达,进而促进胃黏膜上皮内瘤变。结论 组蛋白H3K27me3沉默子信号丢失是HGIN表观重塑特征之一,沉默子丢失可能与PGK1等糖酵解和氨基酸代谢基因表达紊乱相关。Objective To characterize the silencers in genomic loci that were labeled by H3K37me3 modification in gastric high-grade intraepithelial neoplasia(HGIN)tissues,and identify their key downstream genes.Methods Gastric mucosa were collected from 48 donors,including 24 patients with HGIN and 24 healthy controls who underwent dndoscopic biopsy or endoscopic gastric mucosal dissection in our hospital.Genomic distribution of histone H3K27me3 modification was retrieved by targeted chromosome Cleavage Under Target&Tagmentation(CUT&Tag)sequencing.Bioinformatics analysis tools were used to compare the characteristics and differences of the silencer signals between the 2 types of tissues.The RNA sequencing data and the public high-through chromosome conformation capture(Hi-C)data were integrated to analyze the target genes regulated by silencer remodeling and their potential biological processes.Results Compared with normal gastric mucosal tissue,the number of H3K27me3 modifications and signal intensity in HGIN tissues were significantly reduced,which was manifested by global remodeling of H3K27me3 signals.High-throughput RNA sequencing and bioinformatics analysis showed that there were a total of 8887 differentially expressed genes for HGIN tissues,including 4335 up-regulated genes and 4552 down-regulated ones,and among them,CTNNB1 and other oncogenes were significantly up-regulated.Integrated analysis of epigenomics and transcriptomics data reveled that extensive remodeling of silencers in HGIN.Loss of silencer may regulate the expression of metabolic genes related to amino acid biosynthesis,arginine and proline metabolism and glycolysis at the transcriptional level,such as phosphoglycerate kinase 1(PGK1),which may promote development of gastric precancerous lesions.Conclusion Global remodeling of silencers,namely loss of H3K27me3 modification,is an epigenomic characteristics of HGIN tissue,which may lead to expression dysregulation of glycolysis and amino acid metabolism regulators,such as PGK1.

关 键 词：胃高级别上皮内瘤变 胃癌 组蛋白修饰H3K27me3 沉默子 磷酸甘油醛激酶1 

分 类 号：R394.3[医药卫生—医学遗传学] R730.23[医药卫生—基础医学] R735.2