IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38528-z.html
   My bibliography  Save this article

Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation

Author

Listed:
  • Qing Li

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Jiansen Lu

    (Peking University)

  • Xidi Yin

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Yunjian Chang

    (Chinese Academy of Sciences)

  • Chao Wang

    (Chinese Academy of Sciences)

  • Meng Yan

    (University of Chinese Academy of Sciences)

  • Li Feng

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Yanbo Cheng

    (Shanghai Tech University)

  • Yun Gao

    (Peking University)

  • Beiying Xu

    (Chinese Academy of Sciences)

  • Yao Zhang

    (Chinese Academy of Sciences)

  • Yingyi Wang

    (Shanghai Tech University)

  • Guizhong Cui

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Luang Xu

    (Chinese Academy of Sciences)

  • Yidi Sun

    (Chinese Academy of Sciences)

  • Rong Zeng

    (Chinese Academy of Sciences)

  • Yixue Li

    (Chinese Academy of Sciences)

  • Naihe Jing

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Guo-Liang Xu

    (Chinese Academy of Sciences)

  • Ligang Wu

    (Chinese Academy of Sciences)

  • Fuchou Tang

    (Peking University)

  • Jinsong Li

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Shanghai Tech University)

Abstract

During embryo development, DNA methylation is established by DNMT3A/3B and subsequently maintained by DNMT1. While much research has been done in this field, the functional significance of DNA methylation in embryogenesis remains unknown. Here, we establish a system of simultaneous inactivation of multiple endogenous genes in zygotes through screening for base editors that can efficiently introduce a stop codon. Embryos with mutations in Dnmts and/or Tets can be generated in one step with IMGZ. Dnmt-null embryos display gastrulation failure at E7.5. Interestingly, although DNA methylation is absent, gastrulation-related pathways are down-regulated in Dnmt-null embryos. Moreover, DNMT1, DNMT3A, and DNMT3B are critical for gastrulation, and their functions are independent of TET proteins. Hypermethylation can be sustained by either DNMT1 or DNMT3A/3B at some promoters, which are related to the suppression of miRNAs. The introduction of a single mutant allele of six miRNAs and paternal IG-DMR partially restores primitive streak elongation in Dnmt-null embryos. Thus, our results unveil an epigenetic correlation between promoter methylation and suppression of miRNA expression for gastrulation and demonstrate that IMGZ can accelerate deciphering the functions of multiple genes in vivo.

Suggested Citation

  • Qing Li & Jiansen Lu & Xidi Yin & Yunjian Chang & Chao Wang & Meng Yan & Li Feng & Yanbo Cheng & Yun Gao & Beiying Xu & Yao Zhang & Yingyi Wang & Guizhong Cui & Luang Xu & Yidi Sun & Rong Zeng & Yixue, 2023. "Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38528-z
    DOI: 10.1038/s41467-023-38528-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38528-z
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-38528-z?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. Johnny H. Hu & Shannon M. Miller & Maarten H. Geurts & Weixin Tang & Liwei Chen & Ning Sun & Christina M. Zeina & Xue Gao & Holly A. Rees & Zhi Lin & David R. Liu, 2018. "Evolved Cas9 variants with broad PAM compatibility and high DNA specificity," Nature, Nature, vol. 556(7699), pages 57-63, April.
    2. Simon Andrews & Christel Krueger & Maravillas Mellado-Lopez & Myriam Hemberger & Wendy Dean & Vicente Perez-Garcia & Courtney W. Hanna, 2023. "Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yvonne Tay & Jinqiu Zhang & Andrew M. Thomson & Bing Lim & Isidore Rigoutsos, 2008. "MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation," Nature, Nature, vol. 455(7216), pages 1124-1128, October.
    4. Rahul M. Kohli & Yi Zhang, 2013. "TET enzymes, TDG and the dynamics of DNA demethylation," Nature, Nature, vol. 502(7472), pages 472-479, October.
    5. Yingzi Cui & Xuehui Lyu & Li Ding & Lan Ke & Dechang Yang & Mehdi Pirouz & Ye Qi & Jennie Ong & Ge Gao & Peng Du & Richard I. Gregory, 2021. "Global miRNA dosage control of embryonic germ layer specification," Nature, Nature, vol. 593(7860), pages 602-606, May.
    6. Guangdun Peng & Shengbao Suo & Guizhong Cui & Fang Yu & Ran Wang & Jun Chen & Shirui Chen & Zhiwen Liu & Guoyu Chen & Yun Qian & Patrick P. L. Tam & Jing-Dong J. Han & Naihe Jing, 2019. "Molecular architecture of lineage allocation and tissue organization in early mouse embryo," Nature, Nature, vol. 572(7770), pages 528-532, August.
    7. Hai-Qiang Dai & Bang-An Wang & Lu Yang & Jia-Jia Chen & Guo-Chun Zhu & Mei-Ling Sun & Hao Ge & Rui Wang & Deborah L. Chapman & Fuchou Tang & Xin Sun & Guo-Liang Xu, 2016. "TET-mediated DNA demethylation controls gastrulation by regulating Lefty–Nodal signalling," Nature, Nature, vol. 538(7626), pages 528-532, October.
    8. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    9. Qiyuan Yang & Ronghong Li & Qifeng Lyu & Li Hou & Zhen Liu & Qiang Sun & Miao Liu & Huijuan Shi & Beiying Xu & Mingru Yin & Zhiguang Yan & Ying Huang & Mofang Liu & Yiping Li & Ligang Wu, 2019. "Single-cell CAS-seq reveals a class of short PIWI-interacting RNAs in human oocytes," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    10. Thomas Dahlet & Andrea Argüeso Lleida & Hala Al Adhami & Michael Dumas & Ambre Bender & Richard P. Ngondo & Manon Tanguy & Judith Vallet & Ghislain Auclair & Anaïs F. Bardet & Michael Weber, 2020. "Genome-wide analysis in the mouse embryo reveals the importance of DNA methylation for transcription integrity," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    11. Stefanie Grosswendt & Helene Kretzmer & Zachary D. Smith & Abhishek Sampath Kumar & Sara Hetzel & Lars Wittler & Sven Klages & Bernd Timmermann & Shankar Mukherji & Alexander Meissner, 2020. "Epigenetic regulator function through mouse gastrulation," Nature, Nature, vol. 584(7819), pages 102-108, August.
    12. Tian-Peng Gu & Fan Guo & Hui Yang & Hai-Ping Wu & Gui-Fang Xu & Wei Liu & Zhi-Guo Xie & Linyu Shi & Xinyi He & Seung-gi Jin & Khursheed Iqbal & Yujiang Geno Shi & Zixin Deng & Piroska E. Szabó & Gerd , 2011. "The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes," Nature, Nature, vol. 477(7366), pages 606-610, September.
    13. Masahiro Kaneda & Masaki Okano & Kenichiro Hata & Takashi Sado & Naomi Tsujimoto & En Li & Hiroyuki Sasaki, 2004. "Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting," Nature, Nature, vol. 429(6994), pages 900-903, June.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Chao Huang & Wenting Zhu & Qing Li & Yuchen Lei & Xi Chen & Shaorui Liu & Dianyu Chen & Lijian Zhong & Feng Gao & Shujie Fu & Danyang He & Jinsong Li & Heping Xu, 2024. "Antibody Fc-receptor FcεR1γ stabilizes cell surface receptors in group 3 innate lymphoid cells and promotes anti-infection immunity," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

    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. 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.
    2. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Marion Rosello & Malo Serafini & Luca Mignani & Dario Finazzi & Carine Giovannangeli & Marina C. Mione & Jean-Paul Concordet & Filippo Del Bene, 2022. "Disease modeling by efficient genome editing using a near PAM-less base editor in vivo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Péter István Kulcsár & András Tálas & Zoltán Ligeti & Eszter Tóth & Zsófia Rakvács & Zsuzsa Bartos & Sarah Laura Krausz & Ágnes Welker & Vanessza Laura Végi & Krisztina Huszár & Ervin Welker, 2023. "A cleavage rule for selection of increased-fidelity SpCas9 variants with high efficiency and no detectable off-targets," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Zeyu Lu & Lingtian Zhang & Qing Mu & Junyang Liu & Yu Chen & Haoyuan Wang & Yanjun Zhang & Rui Su & Ruijun Wang & Zhiying Wang & Qi Lv & Zhihong Liu & Jiasen Liu & Yunhua Li & Yanhong Zhao, 2024. "Progress in Research and Prospects for Application of Precision Gene-Editing Technology Based on CRISPR–Cas9 in the Genetic Improvement of Sheep and Goats," Agriculture, MDPI, vol. 14(3), pages 1-17, March.
    6. Lin Zhao & Sabrina R. T. Koseki & Rachel A. Silverstein & Nadia Amrani & Christina Peng & Christian Kramme & Natasha Savic & Martin Pacesa & Tomás C. Rodríguez & Teodora Stan & Emma Tysinger & Lauren , 2023. "PAM-flexible genome editing with an engineered chimeric Cas9," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    7. Jian Wang & Ke Wang & Zhe Deng & Zhiyu Zhong & Guo Sun & Qing Mei & Fuling Zhou & Zixin Deng & Yuhui Sun, 2024. "Engineered cytosine base editor enabling broad-scope and high-fidelity gene editing in Streptomyces," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Simon Andrews & Christel Krueger & Maravillas Mellado-Lopez & Myriam Hemberger & Wendy Dean & Vicente Perez-Garcia & Courtney W. Hanna, 2023. "Mechanisms and function of de novo DNA methylation in placental development reveals an essential role for DNMT3B," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    9. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Luke Hoberecht & Pirunthan Perampalam & Aaron Lun & Jean-Philippe Fortin, 2022. "A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    11. Ariane Lismer & Sarah Kimmins, 2023. "Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    12. Annabel K. Sangree & Audrey L. Griffith & Zsofia M. Szegletes & Priyanka Roy & Peter C. DeWeirdt & Mudra Hegde & Abby V. McGee & Ruth E. Hanna & John G. Doench, 2022. "Benchmarking of SpCas9 variants enables deeper base editor screens of BRCA1 and BCL2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Maarten H. Geurts & Shashank Gandhi & Matteo G. Boretto & Ninouk Akkerman & Lucca L. M. Derks & Gijs Son & Martina Celotti & Sarina Harshuk-Shabso & Flavia Peci & Harry Begthel & Delilah Hendriks & Pa, 2023. "One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Kentaro Mochizuki & Jafar Sharif & Kenjiro Shirane & Kousuke Uranishi & Aaron B. Bogutz & Sanne M. Janssen & Ayumu Suzuki & Akihiko Okuda & Haruhiko Koseki & Matthew C. Lorincz, 2021. "Repression of germline genes by PRC1.6 and SETDB1 in the early embryo precedes DNA methylation-mediated silencing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    15. Irina Arnaoutova & Yvonne Aratyn-Schaus & Lisa Zhang & Michael S. Packer & Hung-Dar Chen & Cheol Lee & Sudeep Gautam & Francine M. Gregoire & Dominique Leboeuf & Steven Boule & Thomas P. Fernandez & V, 2024. "Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Liu Yang & San-Jian Yu & Qi Hong & Yu Yang & Zhi-Ming Shao, 2015. "Reduced Expression of TET1, TET2, TET3 and TDG mRNAs Are Associated with Poor Prognosis of Patients with Early Breast Cancer," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-10, July.
    17. Chengdong Zhang & Yuan Yang & Tao Qi & Yuening Zhang & Linghui Hou & Jingjing Wei & Jingcheng Yang & Leming Shi & Sang-Ging Ong & Hongyan Wang & Hui Wang & Bo Yu & Yongming Wang, 2023. "Prediction of base editor off-targets by deep learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    18. Grace N. Hibshman & Jack P. K. Bravo & Matthew M. Hooper & Tyler L. Dangerfield & Hongshan Zhang & Ilya J. Finkelstein & Kenneth A. Johnson & David W. Taylor, 2024. "Unraveling the mechanisms of PAMless DNA interrogation by SpRY-Cas9," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    19. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    20. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(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_s41467-023-38528-z. 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.