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

Autor: Mortenson KL; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Dawes C; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA., Wilson ER; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Patchen NE; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA., Johnson HE; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Cell Biology and Physiology, Brigham Young University, Provo, UT, USA., Gertz J; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Bailey SD; Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.; Department of Surgery and Human Genetics, McGill University, Montreal, QC, Canada., Liu Y; Department of Biochemistry, University of Utah, Salt Lake City, UT, USA., Varley KE; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Katherine.Varley@hci.utah.edu., Zhang X; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Xiaoyang.Zhang@hci.utah.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 20; Vol. 15 (1), pp. 6130. Date of Electronic Publication: 2024 Jul 20.
DOI: 10.1038/s41467-024-50387-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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