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1.
bioRxiv ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38328209

RESUMO

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.

2.
Nat Commun ; 15(1): 6130, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-39033128

RESUMO

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.


Assuntos
Elementos Facilitadores Genéticos , Regulação Neoplásica da Expressão Gênica , Genômica , Oncogenes , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc , Receptor ErbB-2 , Humanos , Elementos Facilitadores Genéticos/genética , Linhagem Celular Tumoral , Regiões Promotoras Genéticas/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Genômica/métodos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia
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