IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29910-4.html
   My bibliography  Save this article

EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma

Author

Listed:
  • Emely Möller

    (Lausanne University Hospital and University of Lausanne)

  • Viviane Praz

    (Lausanne University Hospital and University of Lausanne)

  • Sanalkumar Rajendran

    (Lausanne University Hospital and University of Lausanne)

  • Rui Dong

    (Massachusetts General Hospital)

  • Alexandra Cauderay

    (Lausanne University Hospital and University of Lausanne
    Massachusetts General Hospital)

  • Yu-Hang Xing

    (Massachusetts General Hospital)

  • Lukuo Lee

    (Massachusetts General Hospital)

  • Carlo Fusco

    (Lausanne University Hospital and University of Lausanne)

  • Liliane C. Broye

    (Lausanne University Hospital and University of Lausanne)

  • Luisa Cironi

    (Lausanne University Hospital and University of Lausanne)

  • Sowmya Iyer

    (Massachusetts General Hospital)

  • Shruthi Rengarajan

    (Massachusetts General Hospital)

  • Mary E. Awad

    (Massachusetts General Hospital)

  • Beverly Naigles

    (Massachusetts General Hospital)

  • Igor Letovanec

    (Central Institute, Valais Hospital
    Lausanne University Hospital and University of Lausanne)

  • Nicola Ormas

    (ASST Sette Laghi)

  • Giovanna Finzi

    (ASST Sette Laghi)

  • Stefano Rosa

    (Lausanne University Hospital and University of Lausanne
    University of Insubria)

  • Fausto Sessa

    (University of Insubria)

  • Ivan Chebib

    (Massachusetts General Hospital and Harvard Medical School)

  • G. Petur Nielsen

    (Massachusetts General Hospital and Harvard Medical School)

  • Antonia Digklia

    (Lausanne University Hospital and University of Lausanne)

  • Dimitrios Spentzos

    (Massachusetts General Hospital)

  • Gregory M. Cote

    (Division of Hematology and Oncology, Massachusetts General Hospital)

  • Edwin Choy

    (Division of Hematology and Oncology, Massachusetts General Hospital)

  • Martin Aryee

    (Massachusetts General Hospital
    Broad Institute)

  • Ivan Stamenkovic

    (Lausanne University Hospital and University of Lausanne)

  • Gaylor Boulay

    (Massachusetts General Hospital)

  • Miguel N. Rivera

    (Massachusetts General Hospital
    Broad Institute)

  • Nicolò Riggi

    (Lausanne University Hospital and University of Lausanne)

Abstract

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.

Suggested Citation

  • Emely Möller & Viviane Praz & Sanalkumar Rajendran & Rui Dong & Alexandra Cauderay & Yu-Hang Xing & Lukuo Lee & Carlo Fusco & Liliane C. Broye & Luisa Cironi & Sowmya Iyer & Shruthi Rengarajan & Mary , 2022. "EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29910-4
    DOI: 10.1038/s41467-022-29910-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29910-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-29910-4?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. Shingo Komura & Kenji Ito & Sho Ohta & Tomoyo Ukai & Mio Kabata & Fumiaki Itakura & Katsunori Semi & Yutaka Matsuda & Kyoichi Hashimoto & Hirofumi Shibata & Masamitsu Sone & Norihide Jo & Kazuya Sekig, 2019. "Cell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    2. Robert E. Thurman & Eric Rynes & Richard Humbert & Jeff Vierstra & Matthew T. Maurano & Eric Haugen & Nathan C. Sheffield & Andrew B. Stergachis & Hao Wang & Benjamin Vernot & Kavita Garg & Sam John &, 2012. "The accessible chromatin landscape of the human genome," Nature, Nature, vol. 489(7414), pages 75-82, September.
    3. Tarjei S. Mikkelsen & Manching Ku & David B. Jaffe & Biju Issac & Erez Lieberman & Georgia Giannoukos & Pablo Alvarez & William Brockman & Tae-Kyung Kim & Richard P. Koche & William Lee & Eric Mendenh, 2007. "Genome-wide maps of chromatin state in pluripotent and lineage-committed cells," Nature, Nature, vol. 448(7153), pages 553-560, August.
    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. Liang-Yu Fu & Tao Zhu & Xinkai Zhou & Ranran Yu & Zhaohui He & Peijing Zhang & Zhigui Wu & Ming Chen & Kerstin Kaufmann & Dijun Chen, 2022. "ChIP-Hub provides an integrative platform for exploring plant regulome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Gaylor Boulay & Liliane C. Broye & Rui Dong & Sowmya Iyer & Rajendran Sanalkumar & Yu-Hang Xing & Rémi Buisson & Shruthi Rengarajan & Beverly Naigles & Benoît Duc & Angela Volorio & Mary E. Awad & Raf, 2024. "EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Linghua Zhou & Yong Shen & Libo Jiang & Danni Yin & Jingxin Guo & Hui Zheng & Hao Sun & Rongling Wu & Yunqian Guo, 2015. "Systems Mapping for Hematopoietic Progenitor Cell Heterogeneity," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-18, May.
    4. Mohammad Jaber & Ahmed Radwan & Netanel Loyfer & Mufeed Abdeen & Shulamit Sebban & Areej Khatib & Hazar Yassen & Thorsten Kolb & Marc Zapatka & Kirill Makedonski & Aurelie Ernst & Tommy Kaplan & Yosef, 2022. "Comparative parallel multi-omics analysis during the induction of pluripotent and trophectoderm states," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    5. Dongjun Chung & Dan Park & Kevin Myers & Jeffrey Grass & Patricia Kiley & Robert Landick & Sündüz Keleş, 2013. "dPeak: High Resolution Identification of Transcription Factor Binding Sites from PET and SET ChIP-Seq Data," PLOS Computational Biology, Public Library of Science, vol. 9(10), pages 1-13, October.
    6. Grigorios Georgolopoulos & Nikoletta Psatha & Mineo Iwata & Andrew Nishida & Tannishtha Som & Minas Yiangou & John A. Stamatoyannopoulos & Jeff Vierstra, 2021. "Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Chet H. Loh & Siebe Genesen & Matteo Perino & Magnus R. Bark & Gert Jan C. Veenstra, 2021. "Loss of PRC2 subunits primes lineage choice during exit of pluripotency," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    8. Han Wang & Huiying Sun & Bilin Liang & Fang Zhang & Fan Yang & Bowen Cui & Lixia Ding & Xiang Wang & Ronghua Wang & Jiaoyang Cai & Yanjing Tang & Jianan Rao & Wenting Hu & Shuang Zhao & Wenyan Wu & Xi, 2023. "Chromatin accessibility landscape of relapsed pediatric B-lineage acute lymphoblastic leukemia," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Phoebe Lut Fei Tam & Ming Fung Cheung & Lu Yan Chan & Danny Leung, 2024. "Cell-type differential targeting of SETDB1 prevents aberrant CTCF binding, chromatin looping, and cis-regulatory interactions," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. Tara N. Yankee & Sungryong Oh & Emma Wentworth Winchester & Andrea Wilderman & Kelsey Robinson & Tia Gordon & Jill A. Rosenfeld & Jennifer VanOudenhove & Daryl A. Scott & Elizabeth J. Leslie & Justin , 2023. "Integrative analysis of transcriptome dynamics during human craniofacial development identifies candidate disease genes," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    11. Xuelong Yao & Zongyang Lu & Zhanying Feng & Lei Gao & Xin Zhou & Min Li & Suijuan Zhong & Qian Wu & Zhenbo Liu & Haofeng Zhang & Zeyuan Liu & Lizhi Yi & Tao Zhou & Xudong Zhao & Jun Zhang & Yong Wang , 2022. "Comparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    12. Daniel Sánchez-Taltavull & Parameswaran Ramachandran & Nelson Lau & Theodore J Perkins, 2016. "Bayesian Correlation Analysis for Sequence Count Data," PLOS ONE, Public Library of Science, vol. 11(10), pages 1-24, October.
    13. Yayoi Natsume-Kitatani & Hiroshi Mamitsuka, 2016. "Classification of Promoters Based on the Combination of Core Promoter Elements Exhibits Different Histone Modification Patterns," PLOS ONE, Public Library of Science, vol. 11(3), pages 1-18, March.
    14. Federica Baccini & Monica Bianchini & Filippo Geraci, 2022. "Graph-Based Integration of Histone Modification Profiles," Mathematics, MDPI, vol. 10(11), pages 1-15, May.
    15. Siqian Feng & Chaitanya Rastogi & Ryan Loker & William J. Glassford & H. Tomas Rube & Harmen J. Bussemaker & Richard S. Mann, 2022. "Transcription factor paralogs orchestrate alternative gene regulatory networks by context-dependent cooperation with multiple cofactors," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Yurika Matsui & Mohamed Nadhir Djekidel & Katherine Lindsay & Parimal Samir & Nina Connolly & Gang Wu & Xiaoyang Yang & Yiping Fan & Beisi Xu & Jamy C. Peng, 2023. "SNIP1 and PRC2 coordinate cell fates of neural progenitors during brain development," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Nikolai Schleussner & Pierre Cauchy & Vedran Franke & Maciej Giefing & Oriol Fornes & Naveen Vankadari & Salam A. Assi & Mariantonia Costanza & Marc A. Weniger & Altuna Akalin & Ioannis Anagnostopoulo, 2023. "Transcriptional reprogramming by mutated IRF4 in lymphoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    18. Hillary Koch & Cheryl A. Keller & Guanjue Xiang & Belinda Giardine & Feipeng Zhang & Yicheng Wang & Ross C. Hardison & Qunhua Li, 2022. "CLIMB: High-dimensional association detection in large scale genomic data," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    19. Alan Selewa & Kaixuan Luo & Michael Wasney & Linsin Smith & Xiaotong Sun & Chenwei Tang & Heather Eckart & Ivan P. Moskowitz & Anindita Basu & Xin He & Sebastian Pott, 2023. "Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. M d Mesbah Uddin & Ngoc Quynh H. Nguyen & Bing Yu & Jennifer A. Brody & Akhil Pampana & Tetsushi Nakao & Myriam Fornage & Jan Bressler & Nona Sotoodehnia & Joshua S. Weinstock & Michael C. Honigberg &, 2022. "Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease," Nature Communications, Nature, vol. 13(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:13:y:2022:i:1:d:10.1038_s41467-022-29910-4. 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.