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<p>Epigenetic modifications on natural chromosomes are inherited and maintained in a default state, making it challenging to remove intrinsic marks to study the fundamental principles of their establishment and further influence on transcriptional regulation. In this study, we developed SynNICE, a method for assembling and delivering intact, naive, synthetic megabase (Mb)-scale human DNA into early mouse embryos, to study de novo epigenetic regulation. By assembling and delivering a 1.14-Mb human <i>AZFa</i> (<i>hAZFa</i>) locus, we observed the spontaneous incorporation of murine histones and the establishment of DNA methylation at the one-cell stage. Notably, DNA methylation from scratch strongly enriches at repeat sequences without H3K9me3 reinforcement. Furthermore, the transcription of <i>hAZFa</i> initiated at the four-cell stage is regulated by newly established DNA methylation. This method provides a unique platform for exploring de novo epigenomic regulation mechanisms in higher animals.</p>

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De novo assembly and delivery of synthetic megabase-scale human DNA into mouse early embryos

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月10日

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  • Yue Liu,
  • Jianting Zhou,
  • Duo Liu,
  • Xiaoyu Hu,
  • Lin Yang,
  • Xue-Ru Song,
  • Xiao-Dong Jin,
  • Wei Xie,
  • Luhan Yang,
  • Zichuan Liu,
  • Ying-Jin Yuan

摘要

Epigenetic modifications on natural chromosomes are inherited and maintained in a default state, making it challenging to remove intrinsic marks to study the fundamental principles of their establishment and further influence on transcriptional regulation. In this study, we developed SynNICE, a method for assembling and delivering intact, naive, synthetic megabase (Mb)-scale human DNA into early mouse embryos, to study de novo epigenetic regulation. By assembling and delivering a 1.14-Mb human AZFa (hAZFa) locus, we observed the spontaneous incorporation of murine histones and the establishment of DNA methylation at the one-cell stage. Notably, DNA methylation from scratch strongly enriches at repeat sequences without H3K9me3 reinforcement. Furthermore, the transcription of hAZFa initiated at the four-cell stage is regulated by newly established DNA methylation. This method provides a unique platform for exploring de novo epigenomic regulation mechanisms in higher animals.