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Cell Rep. 2019 Jan 8;26(2):302-312.e4. doi: 10.1016/j.celrep.2018.12.046.

Base-Editing-Mediated R17H Substitution in Histone H3 Reveals Methylation-Dependent Regulation of Yap Signaling and Early Mouse Embryo Development.

Author information

1
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
2
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
4
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
5
School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. Electronic address: huangxx@shanghaitech.edu.cn.
6
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: huiyang@ion.ac.cn.
7
Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510006, China. Electronic address: ybqiao@gzhu.edu.cn.

Abstract

The coactivator-associated arginine methyltransferase CARM1 catalyzes the methylation of histone H3 arginine 17/26 (H3R17/26me) and non-histone proteins at arginine residues to regulate gene transactivation through profiling or Carm1 overexpression assays. However, the direct relationship between H3R17/26me and its causal role in mouse embryo development remains largely unclear. Here, we use rAPOBEC1-XTEN-Cas9n-UGI (BE3) to efficiently introduce a point mutation (R17H) at multiple Hist1/2H3 loci and a premature-stop codon into the catalytic domain of CARM1 in mouse embryos, resulting in remarkable downregulation of H3R17me levels and developmental defects in pre-implantation and fetal embryos. Transcriptomic analysis reveals that Yap1 and cell cycle signaling pathways are dysregulated in Carm1 truncation and H3R17H substitution embryos, and Yap1 overexpression could rescue the base-editing-elicited defects. Our data establish the direct regulatory relationship between CARM1-mediated H3R17me and early mouse embryo development and demonstrate that Yap1 acts downstream of CARM1-mediated H3R17me to regulate the mouse embryo development.

KEYWORDS:

CARM1; H3R17; Yap1 signaling; base editing; embryo development; histone methylation

PMID:
30625312
DOI:
10.1016/j.celrep.2018.12.046
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