IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36150-7.html
   My bibliography  Save this article

Chromatin complex dependencies reveal targeting opportunities in leukemia

Author

Listed:
  • Fadi J. Najm

    (Broad Institute of MIT and Harvard)

  • Peter DeWeirdt

    (Broad Institute of MIT and Harvard)

  • Molly M. Moore

    (Broad Institute of MIT and Harvard)

  • Samantha M. Bevill

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Chadi A. El Farran

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Kevin A. Macias

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Mudra Hegde

    (Broad Institute of MIT and Harvard)

  • Amanda L. Waterbury

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Brian B. Liau

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Peter Galen

    (Brigham and Women’s Hospital)

  • John G. Doench

    (Broad Institute of MIT and Harvard)

  • Bradley E. Bernstein

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.

Suggested Citation

  • Fadi J. Najm & Peter DeWeirdt & Molly M. Moore & Samantha M. Bevill & Chadi A. El Farran & Kevin A. Macias & Mudra Hegde & Amanda L. Waterbury & Brian B. Liau & Peter Galen & John G. Doench & Bradley , 2023. "Chromatin complex dependencies reveal targeting opportunities in leukemia," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36150-7
    DOI: 10.1038/s41467-023-36150-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36150-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-36150-7?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. Zhenglong Gu & Lars M. Steinmetz & Xun Gu & Curt Scharfe & Ronald W. Davis & Wen-Hsiung Li, 2003. "Role of duplicate genes in genetic robustness against null mutations," Nature, Nature, vol. 421(6918), pages 63-66, January.
    2. Laura MacPherson & Juliana Anokye & Miriam M. Yeung & Enid Y. N. Lam & Yih-Chih Chan & Chen-Fang Weng & Paul Yeh & Kathy Knezevic & Miriam S. Butler & Annabelle Hoegl & Kah-Lok Chan & Marian L. Burr &, 2020. "HBO1 is required for the maintenance of leukaemia stem cells," Nature, Nature, vol. 577(7789), pages 266-270, January.
    3. W. Frank Lenoir & Micaela Morgado & Peter C. DeWeirdt & Megan McLaughlin & Audrey L. Griffith & Annabel K. Sangree & Marissa N. Feeley & Nazanin Esmaeili Anvar & Eiru Kim & Lori L. Bertolet & Medina C, 2021. "Discovery of putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in acute myeloid leukemia cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Ralph Stadhouders & Guillaume J. Filion & Thomas Graf, 2019. "Transcription factors and 3D genome conformation in cell-fate decisions," Nature, Nature, vol. 569(7756), pages 345-354, May.
    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. Nazanin Esmaeili Anvar & Chenchu Lin & Xingdi Ma & Lori L. Wilson & Ryan Steger & Annabel K. Sangree & Medina Colic & Sidney H. Wang & John G. Doench & Traver Hart, 2024. "Efficient gene knockout and genetic interaction screening using the in4mer CRISPR/Cas12a multiplex knockout platform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Maria A. Missinato & Sean Murphy & Michaela Lynott & Michael S. Yu & Anaïs Kervadec & Yu-Ling Chang & Suraj Kannan & Mafalda Loreti & Christopher Lee & Prashila Amatya & Hiroshi Tanaka & Chun-Teng Hua, 2023. "Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Jiaxi Zhao & Nicholas C. Lammers & Simon Alamos & Yang Joon Kim & Gabriella Martini & Hernan G. Garcia, 2024. "Optogenetic dissection of transcriptional repression in a multicellular organism," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Miquel Anglada-Girotto & Ludovica Ciampi & Sophie Bonnal & Sarah A. Head & Samuel Miravet-Verde & Luis Serrano, 2024. "In silico RNA isoform screening to identify potential cancer driver exons with therapeutic applications," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    5. Malaguti, Giulia & Singh, Param Priya & Isambert, Hervé, 2014. "On the retention of gene duplicates prone to dominant deleterious mutations," Theoretical Population Biology, Elsevier, vol. 93(C), pages 38-51.
    6. Hao Li & Zebei Han & Yu Sun & Fu Wang & Pengzhen Hu & Yuang Gao & Xuemei Bai & Shiyu Peng & Chao Ren & Xiang Xu & Zeyu Liu & Hebing Chen & Yang Yang & Xiaochen Bo, 2024. "CGMega: explainable graph neural network framework with attention mechanisms for cancer gene module dissection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    7. Jayme L. Dahlin & Bruce K. Hua & Beth E. Zucconi & Shawn D. Nelson & Shantanu Singh & Anne E. Carpenter & Jonathan H. Shrimp & Evelyne Lima-Fernandes & Mathias J. Wawer & Lawrence P. W. Chung & Ayushi, 2023. "Reference compounds for characterizing cellular injury in high-content cellular morphology assays," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    8. Ki-Hong Jung & Jinwon Lee & Chris Dardick & Young-Su Seo & Peijian Cao & Patrick Canlas & Jirapa Phetsom & Xia Xu & Shu Ouyang & Kyungsook An & Yun-Ja Cho & Geun-Cheol Lee & Yoosook Lee & Gynheung An , 2008. "Identification and Functional Analysis of Light-Responsive Unique Genes and Gene Family Members in Rice," PLOS Genetics, Public Library of Science, vol. 4(8), pages 1-19, August.
    9. Gabrielle A. Dotson & Can Chen & Stephen Lindsly & Anthony Cicalo & Sam Dilworth & Charles Ryan & Sivakumar Jeyarajan & Walter Meixner & Cooper Stansbury & Joshua Pickard & Nicholas Beckloff & Amit Su, 2022. "Deciphering multi-way interactions in the human genome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Tomas Zelenka & Antonios Klonizakis & Despina Tsoukatou & Dionysios-Alexandros Papamatheakis & Sören Franzenburg & Petros Tzerpos & Ioannis-Rafail Tzonevrakis & George Papadogkonas & Manouela Kapsetak, 2022. "The 3D enhancer network of the developing T cell genome is shaped by SATB1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    11. Joseph Bozorgmehr, 2012. "Natural selection as a paradigm of opportunism in biology," Journal of Bioeconomics, Springer, vol. 14(1), pages 61-75, April.
    12. Mattia Zaghi & Federica Banfi & Luca Massimino & Monica Volpin & Edoardo Bellini & Simone Brusco & Ivan Merelli & Cristiana Barone & Michela Bruni & Linda Bossini & Luigi Antonio Lamparelli & Laura Pi, 2023. "Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    13. Wen Jun Xie & Yifeng Qi & Bin Zhang, 2020. "Characterizing chromatin folding coordinate and landscape with deep learning," PLOS Computational Biology, Public Library of Science, vol. 16(9), pages 1-19, September.
    14. Mingsen Li & Huizhen Guo & Bofeng Wang & Zhuo Han & Siqi Wu & Jiafeng Liu & Huaxing Huang & Jin Zhu & Fengjiao An & Zesong Lin & Kunlun Mo & Jieying Tan & Chunqiao Liu & Li Wang & Xin Deng & Guigang L, 2024. "The single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    15. Yosuke Komata & Akinori Kanai & Takahiro Maeda & Toshiya Inaba & Akihiko Yokoyama, 2023. "MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    16. Andras Gyorgy, 2023. "Competition and evolutionary selection among core regulatory motifs in gene expression control," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    17. Hui Wang & Boyuan Li & Linyu Zuo & Bo Wang & Yan Yan & Kai Tian & Rong Zhou & Chenlu Wang & Xizi Chen & Yongpeng Jiang & Haonan Zheng & Fangfei Qin & Bin Zhang & Yang Yu & Chao-Pei Liu & Yanhui Xu & J, 2022. "The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    18. Alon Kaufman & Alon Keinan & Isaac Meilijson & Martin Kupiec & Eytan Ruppin, 2005. "Quantitative Analysis of Genetic and Neuronal Multi-Perturbation Experiments," PLOS Computational Biology, Public Library of Science, vol. 1(6), pages 1-7, November.
    19. Zhi Liu & Dong-Sung Lee & Yuqiong Liang & Ye Zheng & Jesse R. Dixon, 2023. "Foxp3 orchestrates reorganization of chromatin architecture to establish regulatory T cell identity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    20. Jiegen Wu & Baoqiang Chen & Yadi Liu & Liang Ma & Wen Huang & Yihan Lin, 2022. "Modulating gene regulation function by chemically controlled transcription factor clustering," Nature Communications, Nature, vol. 13(1), pages 1-15, 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:14:y:2023:i:1:d:10.1038_s41467-023-36150-7. 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.