3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression

Abstract

ABSTRACTCancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that are hijacked to activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) to characterize enhancer hijacking. HAPI analysis of HiChIP data from 34 cancer cell lines identified enhancer hijacking events that activate both known and potentially novel oncogenes such asMYC, CCND1,ETV1,CRKL, andID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often includingMYC, on the same complex amplicons such as ecDNA. We characterized aMYC-ERBB2chimeric ecDNA, in whichERBB2heavily hijacksMYC’s enhancers. Notably, CRISPRi of theMYCpromoter led to increased interaction ofERBB2withMYCenhancers and elevatedERBB2expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.