IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-43264-5.html
   My bibliography  Save this article

Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens

Author

Listed:
  • Shaela Wright

    (St. Jude Children’s Research Hospital)

  • Xujie Zhao

    (St. Jude Children’s Research Hospital
    Advanced Institute for Life and Health, Southeast University)

  • Wojciech Rosikiewicz

    (St. Jude Children’s Research Hospital)

  • Shelby Mryncza

    (Rhodes College)

  • Judith Hyle

    (St. Jude Children’s Research Hospital)

  • Wenjie Qi

    (St. Jude Children’s Research Hospital)

  • Zhenling Liu

    (St. Jude Children’s Research Hospital)

  • Siqi Yi

    (St. Jude Children’s Research Hospital)

  • Yong Cheng

    (St. Jude Children’s Research Hospital)

  • Beisi Xu

    (St. Jude Children’s Research Hospital)

  • Chunliang Li

    (St. Jude Children’s Research Hospital)

Abstract

Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.

Suggested Citation

  • Shaela Wright & Xujie Zhao & Wojciech Rosikiewicz & Shelby Mryncza & Judith Hyle & Wenjie Qi & Zhenling Liu & Siqi Yi & Yong Cheng & Beisi Xu & Chunliang Li, 2023. "Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43264-5
    DOI: 10.1038/s41467-023-43264-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-43264-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-43264-5?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. Liling Wan & Hong Wen & Yuanyuan Li & Jie Lyu & Yuanxin Xi & Takayuki Hoshii & Julia K. Joseph & Xiaolu Wang & Yong-Hwee E. Loh & Michael A. Erb & Amanda L. Souza & James E. Bradner & Li Shen & Wei Li, 2017. "ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia," Nature, Nature, vol. 543(7644), pages 265-269, March.
    2. Silvana Konermann & Mark D. Brigham & Alexandro E. Trevino & Julia Joung & Omar O. Abudayyeh & Clea Barcena & Patrick D. Hsu & Naomi Habib & Jonathan S. Gootenberg & Hiroshi Nishimasu & Osamu Nureki &, 2015. "Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex," Nature, Nature, vol. 517(7536), pages 583-588, January.
    3. Henry E. Pelish & Brian B. Liau & Ioana I. Nitulescu & Anupong Tangpeerachaikul & Zachary C. Poss & Diogo H. Da Silva & Brittany T. Caruso & Alexander Arefolov & Olugbeminiyi Fadeyi & Amanda L. Christ, 2015. "Mediator kinase inhibition further activates super-enhancer-associated genes in AML," Nature, Nature, vol. 526(7572), pages 273-276, October.
    4. Laura Godfrey & Nicholas T. Crump & Ross Thorne & I-Jun Lau & Emmanouela Repapi & Dimitra Dimou & Alastair L. Smith & Joe R. Harman & Jelena M. Telenius & A. Marieke Oudelaar & Damien J. Downes & Pare, 2019. "DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation," Nature Communications, Nature, vol. 10(1), pages 1-15, 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. Siobhan Rice & Thomas Jackson & Nicholas T. Crump & Nicholas Fordham & Natalina Elliott & Sorcha O’Byrne & Maria del Mar Lara Fanego & Dilys Addy & Trisevgeni Crabb & Carryl Dryden & Sarah Inglott & D, 2021. "A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Chih-Hao Wang & Tadataka Tsuji & Li-Hong Wu & Cheng-Ying Yang & Tian Lian Huang & Mari Sato & Farnaz Shamsi & Yu-Hua Tseng, 2024. "Endothelin 3/EDNRB signaling induces thermogenic differentiation of white adipose tissue," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    5. Xiangfeng Kong & Hainan Zhang & Guoling Li & Zikang Wang & Xuqiang Kong & Lecong Wang & Mingxing Xue & Weihong Zhang & Yao Wang & Jiajia Lin & Jingxing Zhou & Xiaowen Shen & Yinghui Wei & Na Zhong & W, 2023. "Engineered CRISPR-OsCas12f1 and RhCas12f1 with robust activities and expanded target range for genome editing," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Jian Wang & Yuxi Teng & Ruihua Zhang & Yifei Wu & Lei Lou & Yusong Zou & Michelle Li & Zhong-Ru Xie & Yajun Yan, 2021. "Engineering a PAM-flexible SpdCas9 variant as a universal gene repressor," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    7. Boris Kantor & Bernadette O’Donovan & Joseph Rittiner & Dellila Hodgson & Nicholas Lindner & Sophia Guerrero & Wendy Dong & Austin Zhang & Ornit Chiba-Falek, 2024. "The therapeutic implications of all-in-one AAV-delivered epigenome-editing platform in neurodegenerative disorders," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Jasmin Bartl & Marco Zanini & Flavia Bernardi & Antoine Forget & Lena Blümel & Julie Talbot & Daniel Picard & Nan Qin & Gabriele Cancila & Qingsong Gao & Soumav Nath & Idriss Mahoungou Koumba & Mariet, 2022. "The HHIP-AS1 lncRNA promotes tumorigenicity through stabilization of dynein complex 1 in human SHH-driven tumors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Kate M. MacDonald & Shirony Nicholson-Puthenveedu & Maha M. Tageldein & Sarika Khasnis & Cheryl H. Arrowsmith & Shane M. Harding, 2023. "Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    10. Steffen Mueller & Gail Dennison & Shujun Liu, 2021. "An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality," IJERPH, MDPI, vol. 18(13), pages 1-23, June.
    11. Zhe Wang & Xin Yang & Delin Chen & Yanqing Liu & Zhiming Li & Shoufu Duan & Zhiguo Zhang & Xuejun Jiang & Brent R. Stockwell & Wei Gu, 2024. "GAS41 modulates ferroptosis by anchoring NRF2 on chromatin," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    12. Edurne San José-Enériz & Naroa Gimenez-Camino & Obdulia Rabal & Leire Garate & Estibaliz Miranda & Nahia Gómez-Echarte & Fernando García & Stella Charalampopoulou & Elena Sáez & Amaia Vilas-Zornoza & , 2024. "Epigenetic-based differentiation therapy for Acute Myeloid Leukemia," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    13. Paola Cattaneo & Michael G. B. Hayes & Nina Baumgarten & Dennis Hecker & Sofia Peruzzo & Galip S. Aslan & Paolo Kunderfranco & Veronica Larcher & Lunfeng Zhang & Riccardo Contu & Gregory Fonseca & Sim, 2022. "DOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    14. Arpiar Saunders & Kee Wui Huang & Cassandra Vondrak & Christina Hughes & Karina Smolyar & Harsha Sen & Adrienne C. Philson & James Nemesh & Alec Wysoker & Seva Kashin & Bernardo L. Sabatini & Steven A, 2022. "Ascertaining cells’ synaptic connections and RNA expression simultaneously with barcoded rabies virus libraries," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    15. William C. W. Chen & Leonid Gaidukov & Yong Lai & Ming-Ru Wu & Jicong Cao & Michael J. Gutbrod & Gigi C. G. Choi & Rachel P. Utomo & Ying-Chou Chen & Liliana Wroblewska & Manolis Kellis & Lin Zhang & , 2022. "A synthetic transcription platform for programmable gene expression in mammalian cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Julia Joung & Paul C. Kirchgatterer & Ankita Singh & Jang H. Cho & Suchita P. Nety & Rebecca C. Larson & Rhiannon K. Macrae & Rebecca Deasy & Yuen-Yi Tseng & Marcela V. Maus & Feng Zhang, 2022. "CRISPR activation screen identifies BCL-2 proteins and B3GNT2 as drivers of cancer resistance to T cell-mediated cytotoxicity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. 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.
    18. Jifeng Yu & Bangguo Zhou & Shen Zhang & Haohao Yin & Liping Sun & Yinying Pu & Boyang Zhou & Yikang Sun & Xiaolong Li & Yan Fang & Lifan Wang & Chongke Zhao & Dou Du & Yan Zhang & Huixiong Xu, 2022. "Design of a self-driven probiotic-CRISPR/Cas9 nanosystem for sono-immunometabolic cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    19. Shengyong Yu & Chunhua Zhou & Jiangping He & Zhaokai Yao & Xingnan Huang & Bowen Rong & Hong Zhu & Shijie Wang & Shuyan Chen & Xialian Wang & Baomei Cai & Guoqing Zhao & Yuhan Chen & Lizhan Xiao & He , 2022. "BMP4 drives primed to naïve transition through PGC-like state," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Liam McAllan & Damir Baranasic & Sergio Villicaña & Scarlett Brown & Weihua Zhang & Benjamin Lehne & Marco Adamo & Andrew Jenkinson & Mohamed Elkalaawy & Borzoueh Mohammadi & Majid Hashemi & Nadia Fer, 2023. "Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes," Nature Communications, Nature, vol. 14(1), pages 1-20, 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_s41467-023-43264-5. 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.