IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50387-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    Brigham Young University)

  • Jason Gertz

    (University of Utah)

  • Swneke D. Bailey

    (Research Institute of the McGill University Health Centre
    McGill University)

  • Yang Liu

    (University of Utah)

  • Katherine E. Varley

    (University of Utah)

  • Xiaoyang Zhang

    (University of Utah)

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.

Suggested Citation

  • Katelyn L. Mortenson & Courtney Dawes & Emily R. Wilson & Nathan E. Patchen & Hailey E. Johnson & Jason Gertz & Swneke D. Bailey & Yang Liu & Katherine E. Varley & Xiaoyang Zhang, 2024. "3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50387-w
    DOI: 10.1038/s41467-024-50387-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50387-w
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50387-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. William A. Flavahan & Yotam Drier & Sarah E. Johnstone & Matthew L. Hemming & Daniel R. Tarjan & Esmat Hegazi & Sarah J. Shareef & Nauman M. Javed & Chandrajit P. Raut & Benjamin K. Eschle & Prafulla , 2019. "Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs," Nature, Nature, vol. 575(7781), pages 229-233, November.
    2. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J.Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Red, 2012. "Addendum: The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 492(7428), pages 290-290, December.
    3. A. Marieke Oudelaar & Caroline L. Harrold & Lars L. P. Hanssen & Jelena M. Telenius & Douglas R. Higgs & Jim R. Hughes, 2019. "A revised model for promoter competition based on multi-way chromatin interactions at the α-globin locus," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    4. Ofer Shoshani & Simon F. Brunner & Rona Yaeger & Peter Ly & Yael Nechemia-Arbely & Dong Hyun Kim & Rongxin Fang & Guillaume A. Castillon & Miao Yu & Julia S. Z. Li & Ying Sun & Mark H. Ellisman & Bing, 2021. "Chromothripsis drives the evolution of gene amplification in cancer," Nature, Nature, vol. 591(7848), pages 137-141, March.
    5. Melissa J. Fullwood & Mei Hui Liu & You Fu Pan & Jun Liu & Han Xu & Yusoff Bin Mohamed & Yuriy L. Orlov & Stoyan Velkov & Andrea Ho & Poh Huay Mei & Elaine G. Y. Chew & Phillips Yao Hui Huang & Willem, 2009. "An oestrogen-receptor-α-bound human chromatin interactome," Nature, Nature, vol. 462(7269), pages 58-64, November.
    6. Paul A. Northcott & Catherine Lee & Thomas Zichner & Adrian M. Stütz & Serap Erkek & Daisuke Kawauchi & David J. H. Shih & Volker Hovestadt & Marc Zapatka & Dominik Sturm & David T. W. Jones & Marcel , 2014. "Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma," Nature, Nature, vol. 511(7510), pages 428-434, July.
    7. Zhichao Xu & Dong-Sung Lee & Sahaana Chandran & Victoria T. Le & Rosalind Bump & Jean Yasis & Sofia Dallarda & Samantha Marcotte & Benjamin Clock & Nicholas Haghani & Chae Yun Cho & Kadir C. Akdemir &, 2022. "Structural variants drive context-dependent oncogene activation in cancer," Nature, Nature, vol. 612(7940), pages 564-572, December.
    8. Mahmoud Ghandi & Franklin W. Huang & Judit Jané-Valbuena & Gregory V. Kryukov & Christopher C. Lo & E. Robert McDonald & Jordi Barretina & Ellen T. Gelfand & Craig M. Bielski & Haoxin Li & Kevin Hu & , 2019. "Next-generation characterization of the Cancer Cell Line Encyclopedia," Nature, Nature, vol. 569(7757), pages 503-508, May.
    9. Jordi Barretina & Giordano Caponigro & Nicolas Stransky & Kavitha Venkatesan & Adam A. Margolin & Sungjoon Kim & Christopher J. Wilson & Joseph Lehár & Gregory V. Kryukov & Dmitriy Sonkin & Anupama Re, 2012. "The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity," Nature, Nature, vol. 483(7391), pages 603-607, March.
    10. King L. Hung & Kathryn E. Yost & Liangqi Xie & Quanming Shi & Konstantin Helmsauer & Jens Luebeck & Robert Schöpflin & Joshua T. Lange & Rocío Chamorro González & Natasha E. Weiser & Celine Chen & Mar, 2021. "ecDNA hubs drive cooperative intermolecular oncogene expression," Nature, Nature, vol. 600(7890), pages 731-736, December.
    11. Esther Rheinbay & Morten Muhlig Nielsen & Federico Abascal & Jeremiah A. Wala & Ofer Shapira & Grace Tiao & Henrik Hornshøj & Julian M. Hess & Randi Istrup Juul & Ziao Lin & Lars Feuerbach & Radhakris, 2020. "Analyses of non-coding somatic drivers in 2,658 cancer whole genomes," Nature, Nature, vol. 578(7793), pages 102-111, February.
    12. Jens Luebeck & Alvin Wei Tian Ng & Patricia C. Galipeau & Xiaohong Li & Carissa A. Sanchez & Annalise C. Katz-Summercorn & Hoon Kim & Sriganesh Jammula & Yudou He & Scott M. Lippman & Roel G. W. Verha, 2023. "Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus," Nature, Nature, vol. 616(7958), pages 798-805, April.
    13. Abhijit Parolia & Marcin Cieslik & Shih-Chun Chu & Lanbo Xiao & Takahiro Ouchi & Yuping Zhang & Xiaoju Wang & Pankaj Vats & Xuhong Cao & Sethuramasundaram Pitchiaya & Fengyun Su & Rui Wang & Felix Y. , 2019. "Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer," Nature, Nature, vol. 571(7765), pages 413-418, July.
    14. Yilong Li & Nicola D. Roberts & Jeremiah A. Wala & Ofer Shapira & Steven E. Schumacher & Kiran Kumar & Ekta Khurana & Sebastian Waszak & Jan O. Korbel & James E. Haber & Marcin Imielinski & Joachim We, 2020. "Patterns of somatic structural variation in human cancer genomes," Nature, Nature, vol. 578(7793), pages 112-121, February.
    15. William A. Flavahan & Yotam Drier & Brian B. Liau & Shawn M. Gillespie & Andrew S. Venteicher & Anat O. Stemmer-Rachamimov & Mario L. Suvà & Bradley E. Bernstein, 2016. "Insulator dysfunction and oncogene activation in IDH mutant gliomas," Nature, Nature, vol. 529(7584), pages 110-114, January.
    16. Ofer Shoshani & Simon F. Brunner & Rona Yaeger & Peter Ly & Yael Nechemia-Arbely & Dong Hyun Kim & Rongxin Fang & Guillaume A. Castillon & Miao Yu & Julia S. Z. Li & Ying Sun & Mark H. Ellisman & Bing, 2021. "Publisher Correction: Chromothripsis drives the evolution of gene amplification in cancer," Nature, Nature, vol. 591(7850), pages 19-19, March.
    17. Scott A. Tomlins & Bharathi Laxman & Saravana M. Dhanasekaran & Beth E. Helgeson & Xuhong Cao & David S. Morris & Anjana Menon & Xiaojun Jing & Qi Cao & Bo Han & Jindan Yu & Lei Wang & James E. Montie, 2007. "Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer," Nature, Nature, vol. 448(7153), pages 595-599, August.
    18. Sihan Wu & Kristen M. Turner & Nam Nguyen & Ramya Raviram & Marcella Erb & Jennifer Santini & Jens Luebeck & Utkrisht Rajkumar & Yarui Diao & Bin Li & Wenjing Zhang & Nathan Jameson & M. Ryan Corces &, 2019. "Circular ecDNA promotes accessible chromatin and high oncogene expression," Nature, Nature, vol. 575(7784), pages 699-703, November.
    19. Konstantin Helmsauer & Maria E. Valieva & Salaheddine Ali & Rocío Chamorro González & Robert Schöpflin & Claudia Röefzaad & Yi Bei & Heathcliff Dorado Garcia & Elias Rodriguez-Fos & Montserrat Puiggrò, 2020. "Enhancer hijacking determines extrachromosomal circular MYCN amplicon architecture in neuroblastoma," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yanli Liu & Zhong Wu & Jin Zhou & Dinesh K. A. Ramadurai & Katelyn L. Mortenson & Estrella Aguilera-Jimenez & Yifei Yan & Xiaojun Yang & Alison M. Taylor & Katherine E. Varley & Jason Gertz & Peter S., 2021. "A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Jinxin Phaedo Chen & Constantin Diekmann & Honggui Wu & Chong Chen & Giulia Chiara & Enrico Berrino & Konstantinos L. Georgiadis & Britta A. M. Bouwman & Mohit Virdi & Luuk Harbers & Sara Erika Bellom, 2024. "scCircle-seq unveils the diversity and complexity of extrachromosomal circular DNAs in single cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Shixiang Wang & Chen-Yi Wu & Ming-Ming He & Jia-Xin Yong & Yan-Xing Chen & Li-Mei Qian & Jin-Ling Zhang & Zhao-Lei Zeng & Rui-Hua Xu & Feng Wang & Qi Zhao, 2024. "Machine learning-based extrachromosomal DNA identification in large-scale cohorts reveals its clinical implications in cancer," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Francesc Muyas & Manuel José Gómez Rodriguez & Rita Cascão & Angela Afonso & Carolin M. Sauer & Claudia C. Faria & Isidro Cortés-Ciriano & Ignacio Flores, 2024. "The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Alexander Martinez-Fundichely & Austin Dixon & Ekta Khurana, 2022. "Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Qionghua Zhu & Xin Zhao & Yuanhang Zhang & Yanping Li & Shang Liu & Jingxuan Han & Zhiyuan Sun & Chunqing Wang & Daqi Deng & Shanshan Wang & Yisen Tang & Yaling Huang & Siyuan Jiang & Chi Tian & Xi Ch, 2023. "Single cell multi-omics reveal intra-cell-line heterogeneity across human cancer cell lines," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Min Wu & Tingting Wang & Nan Ji & Ting Lu & Ran Yuan & Lingxiang Wu & Junxia Zhang & Mengyuan Li & Penghui Cao & Jiarui Zhao & Guanzhang Li & Jianyu Li & Yu Li & Yujie Tang & Zhengliang Gao & Xiuxing , 2024. "Multi-omics and pharmacological characterization of patient-derived glioma cell lines," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Caitlin E. Mills & Kartik Subramanian & Marc Hafner & Mario Niepel & Luca Gerosa & Mirra Chung & Chiara Victor & Benjamin Gaudio & Clarence Yapp & Ajit J. Nirmal & Nicholas Clark & Peter K. Sorger, 2022. "Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    9. Fengju Chen & Yiqun Zhang & Darshan S. Chandrashekar & Sooryanarayana Varambally & Chad J. Creighton, 2023. "Global impact of somatic structural variation on the cancer proteome," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Adrià Fernández-Torras & Miquel Duran-Frigola & Martino Bertoni & Martina Locatelli & Patrick Aloy, 2022. "Integrating and formatting biomedical data as pre-calculated knowledge graph embeddings in the Bioteque," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Chunyang Bao & Richard W. Tourdot & Gregory J. Brunette & Chip Stewart & Lili Sun & Hideo Baba & Masayuki Watanabe & Agoston T. Agoston & Kunal Jajoo & Jon M. Davison & Katie S. Nason & Gad Getz & Ken, 2023. "Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    12. Alvin Wei Tian Ng & Dylan Peter McClurg & Ben Wesley & Shahriar A. Zamani & Emily Black & Ahmad Miremadi & Olivier Giger & Rogier ten Hoopen & Ginny Devonshire & Aisling M. Redmond & Nicola Grehan & S, 2024. "Disentangling oncogenic amplicons in esophageal adenocarcinoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    13. George Rosenberger & Wenxue Li & Mikko Turunen & Jing He & Prem S. Subramaniam & Sergey Pampou & Aaron T. Griffin & Charles Karan & Patrick Kerwin & Diana Murray & Barry Honig & Yansheng Liu & Andrea , 2024. "Network-based elucidation of colon cancer drug resistance mechanisms by phosphoproteomic time-series analysis," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    14. Kelsy C. Cotto & Yang-Yang Feng & Avinash Ramu & Megan Richters & Sharon L. Freshour & Zachary L. Skidmore & Huiming Xia & Joshua F. McMichael & Jason Kunisaki & Katie M. Campbell & Timothy Hung-Po Ch, 2023. "Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    15. Xue-Ke Zhao & Pengwei Xing & Xin Song & Miao Zhao & Linxuan Zhao & Yonglong Dang & Ling-Ling Lei & Rui-Hua Xu & Wen-Li Han & Pan-Pan Wang & Miao-Miao Yang & Jing-Feng Hu & Kan Zhong & Fu-You Zhou & Xu, 2021. "Focal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    16. Noha A. M. Shendy & Melissa Bikowitz & Logan H. Sigua & Yang Zhang & Audrey Mercier & Yousef Khashana & Stephanie Nance & Qi Liu & Ian M. Delahunty & Sarah Robinson & Vanshita Goel & Matthew G. Rees &, 2024. "Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Han Jin & Cheng Zhang & Martin Zwahlen & Kalle Feilitzen & Max Karlsson & Mengnan Shi & Meng Yuan & Xiya Song & Xiangyu Li & Hong Yang & Hasan Turkez & Linn Fagerberg & Mathias Uhlén & Adil Mardinoglu, 2023. "Systematic transcriptional analysis of human cell lines for gene expression landscape and tumor representation," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Robin Aguilar & Conor K. Camplisson & Qiaoyi Lin & Karen H. Miga & William S. Noble & Brian J. Beliveau, 2024. "Tigerfish designs oligonucleotide-based in situ hybridization probes targeting intervals of highly repetitive DNA at the scale of genomes," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    19. Seungyeul Yoo & Abhilasha Sinha & Dawei Yang & Nasser K. Altorki & Radhika Tandon & Wenhui Wang & Deebly Chavez & Eunjee Lee & Ayushi S. Patel & Takashi Sato & Ranran Kong & Bisen Ding & Eric E. Schad, 2022. "Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    20. Alon Stern & Mariam Fokra & Boris Sarvin & Ahmad Abed Alrahem & Won Dong Lee & Elina Aizenshtein & Nikita Sarvin & Tomer Shlomi, 2023. "Inferring mitochondrial and cytosolic metabolism by coupling isotope tracing and deconvolution," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50387-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.