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. 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.
    2. 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.
    3. 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.
    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. Derek H. Janssens & Melodie Duran & Dominik J. Otto & Weifang Wu & Yiling Xu & Danielle Kirkey & Charles G. Mullighan & Joanna S. Yi & Soheil Meshinchi & Jay F. Sarthy & Kami Ahmad & Steven Henikoff, 2024. "MLL oncoprotein levels influence leukemia lineage identities," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Tian Zhou & Xinyi Zhu & Zhizhong Ye & Yong-Fei Wang & Chao Yao & Ning Xu & Mi Zhou & Jianyang Ma & Yuting Qin & Yiwei Shen & Yuanjia Tang & Zhihua Yin & Hong Xu & Yutong Zhang & Xiaoli Zang & Huihua D, 2022. "Lupus enhancer risk variant causes dysregulation of IRF8 through cooperative lncRNA and DNA methylation machinery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. 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.
    4. Haipeng Fu & Tingyu Wang & Xiaohui Kong & Kun Yan & Yang Yang & Jingyi Cao & Yafei Yuan & Nan Wang & Kehkooi Kee & Zhi John Lu & Qiaoran Xi, 2022. "A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. 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.
    6. Yafeng Wang & Guiquan Zhang & Qingzhou Meng & Shisheng Huang & Panpan Guo & Qibin Leng & Lingyun Sun & Geng Liu & Xingxu Huang & Jianghuai Liu, 2022. "Precise tumor immune rewiring via synthetic CRISPRa circuits gated by concurrent gain/loss of transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    7. 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.
    8. 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.
    9. 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.
    10. 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.
    11. Deqiang Kong & Yang Zhou & Yu Wei & Xinyi Wang & Qin Huang & Xianyun Gao & Hang Wan & Mengyao Liu & Liping Kang & Guiling Yu & Jianli Yin & Ningzi Guan & Haifeng Ye, 2024. "Exploring plant-derived phytochrome chaperone proteins for light-switchable transcriptional regulation in mammals," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. 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.
    13. Anna Gogleva & Dimitris Polychronopoulos & Matthias Pfeifer & Vladimir Poroshin & Michaël Ughetto & Matthew J. Martin & Hannah Thorpe & Aurelie Bornot & Paul D. Smith & Ben Sidders & Jonathan R. Dry &, 2022. "Knowledge graph-based recommendation framework identifies drivers of resistance in EGFR mutant non-small cell lung cancer," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Rui Chen & Xinyao Shi & Xiangrui Yao & Tong Gao & Guangyu Huang & Duo Ning & Zemin Cao & Youxin Xu & Weizheng Liang & Simon Zhongyuan Tian & Qionghua Zhu & Liang Fang & Meizhen Zheng & Yuhui Hu & Huan, 2024. "Specific multivalent molecules boost CRISPR-mediated transcriptional activation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    15. 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.
    16. Amy J. Heidersbach & Kristel M. Dorighi & Javier A. Gomez & Ashley M. Jacobi & Benjamin Haley, 2023. "A versatile, high-efficiency platform for CRISPR-based gene activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    17. 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.
    18. 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.
    19. 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.
    20. Xuemei Bai & Chao Sui & Feng Liu & Tian Chen & Lei Zhang & Yi Zheng & Bingyu Liu & Chengjiang Gao, 2022. "The protein arginine methyltransferase PRMT9 attenuates MAVS activation through arginine methylation," 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: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.