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

Katelyn L. Mortenson, Courtney Dawes, Emily R. Wilson, Nathan E. Patchen, Hailey E. Johnson, Jason Gertz, Swneke D. Bailey, Yang Liu, Katherine E. Varley () and Xiaoyang Zhang ()
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Katelyn L. Mortenson: University of Utah
Courtney Dawes: University of Utah
Emily R. Wilson: University of Utah
Nathan E. Patchen: University of Utah
Hailey E. Johnson: University of Utah
Jason Gertz: University of Utah
Swneke D. Bailey: Research Institute of the McGill University Health Centre
Yang Liu: University of Utah
Katherine E. Varley: University of Utah
Xiaoyang Zhang: University of Utah

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Cancer 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 as MYC, CCND1, ETV1, CRKL, and ID4. Furthermore, we found enhancer hijacking among multiple oncogenes from different chromosomes, often including MYC, on the same complex amplicons such as ecDNA. We characterized a MYC-ERBB2 chimeric ecDNA, in which ERBB2 heavily hijacks MYC’s enhancers. Notably, CRISPRi of the MYC promoter led to increased interaction of ERBB2 with MYC enhancers and elevated ERBB2 expression. Our HAPI analysis tool provides a robust strategy to detect enhancer hijacking and reveals novel insights into oncogene activation.

Date: 2024
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DOI: 10.1038/s41467-024-50387-w

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