染色质交互图谱识别癌症中增强子重复的致癌靶点

Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer

GENOME RESEARCH

影响因子:5.5

分区:生物学1区 Top / 生物工程与应用微生物1区生化与分子生物学2区遗传学2区

发表日期:2024 Oct 29

作者: Yueqiang Song, Fuyuan Li, Shangzi Wang, Yuntong Wang, Cong Lai, Lian Chen, Ning Jiang, Jin Li, Xingdong Chen, Swneke D Bailey, Xiaoyang Zhang

DOI: 10.1101/gr.278418.123

摘要

作为结构变异的一种主要类型，串联重复在肿瘤发生中起着关键作用，主要通过增加癌基因的剂量实现。近期研究发现，非编码增强子也受到重复影响，从而激活位于或超出重复区域内的癌基因。然而，增强子重复的普遍性及其靶基因的具体身份在癌症基因组中仍 largely 未明。在此，我们通过非基因中心的全基因组测序数据分析，识别出13种主要癌症类型中的881个重复热点，大部分不包含蛋白编码基因。研究显示，这些热点区域富含远端增强子元素，并具有高度的谱系特异性。我们开发了一种基于HiChIP的方法，能够导航增强子-启动子接触图，从而优先筛选这些热点区域中的靶基因。该方法鉴定出许多新型的增强子重复事件，激活如ESR1、FOXA1、GATA3、GATA6、TP63和VEGFA等癌基因，以及潜在的新癌基因，如GRHL2、IRF2BP2和CREB3L1。特别值得一提的是，在染色体10p15的重复热点中，包含一簇增强子，借助长程染色质相互作用，绕过两个基因，激活了NET1基因的致癌异构体，促进胃癌细胞迁移。专注于串联重复，本研究显著扩展了多种癌症类型中非编码驱动突变的目录，为功能特性分析和治疗干预提供了有吸引力的靶点。

Abstract

As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer-promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1 In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention.