The 11th International Symposium on 3D Genomics

46 / 2024-10-10 20:10:21

Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer

tandem duplication,enhancer

Protein-coding genes constitute only about 1.5% of the entire genome, with noncoding regions that account for the majority of the human genome. Noncoding regions harbor regulatory elements such as enhancers, promoters, silencers and insulators that control the expression of protein-coding genes. Recent work has shown that noncoding enhancers are also critical subjects of duplications in cancer. For instance, distal enhancers of oncogenes such as KLF5, AR, SOX2, MYC and EGFR are selectively duplicated with or without the oncogenes in diverse cancer types, which activates their expression through long-distance enhancer-promoter interactions. These findings demonstrated the critical roles of enhancer elements and their associated enhancer-promoter interactions in the oncogenic duplication events.

Despite their significance, the occurrence of tandem-duplicated enhancers and their complex interactions with target genes remain unclear in various cancer genomes. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identified 881 duplication hotspots that are enriched with distal enhancer elements and are highly lineage-specific across 13 cancer types, most of which do not contain intact protein-coding genes. Also, we proposed a methodology called RENC that utilizes HiChIP results to prioritize target genes for the duplicated enhancers. The accuracy and robustness of the RENC method were validated by assessing previously characterized enhancer duplications for KLF5 in squamous cancer cell lines and AR in prostate cancer cell lines. Using this methodology, we identified 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 identified 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.