染色质相互作用图确定了癌症增强子重复的致癌靶标
Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer
影响因子:5.50000
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
摘要
作为主要类型的结构变体，串联重复通过增加癌基剂量在肿瘤发生中起关键作用。最近的工作表明，非编码增强子也受到重复的影响，导致重复区域内或外部的癌基因激活。然而，增强子重复的流行率及其靶基因的身份在癌症基因组中基本上仍然未知。在这里，通过以非基因方式分析全基因组测序数据，我们在13种主要的癌症类型中确定了881个重复热点，其中大多数不包含蛋白质编码基因。我们表明，热点富含远端增强子元素，并且具有高度的谱系特异性。我们开发了一种基于HICHIP的方法，该方法可导航增强器启动器接触图，以优先考虑具有增强子元素的重复热点的目标基因。 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通过远程染色质相互作用，两个基因激活Net1基因的致癌同工型，以促进胃癌细胞的迁移。我们的研究重点是串联重复，大大扩展了多种癌症类型中非编码驱动因素改变的目录，揭示了功能表征和治疗干预的有吸引力的目标。
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.