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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Catalytic Domain
  • Cell Cycle
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Embryonic Development*
  • Gene Expression Regulation, Developmental*
  • Histone Code
  • Histones / chemistry
  • Histones / genetics
  • Histones / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mutation, Missense
  • Protein-Arginine N-Methyltransferases / chemistry
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism
  • Signal Transduction*
  • Transcriptome
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Histones
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1