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

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 Li, Naihe Jing, Guo-Liang Xu (), Ligang Wu (), Fuchou Tang () and Jinsong Li ()
Additional contact information
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
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

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38528-z

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