Histone chaperone CAF-1 mediates repressive histone modifications to protect preimplantation mouse embryos from endogenous retrotransposons

Yuki Hatanaka, Kimiko Inoue, Mami Oikawa, Satoshi Kamimura, Narumi Ogonuki, Eiichi N. Kodama, Yasuyuki Ohkawa, Yu Ichi Tsukada, Atsuo Ogura

研究成果: Article査読

44 被引用数 (Scopus)

抄録

Substantial proportions of mammalian genomes comprise repetitive elements including endogenous retrotransposons. Although these play diverse roles during development, their appropriate silencing is critically important in maintaining genomic integrity in the host cells. The major mechanism for retrotransposon silencing is DNA methylation, but the wave of global DNA demethylation that occurs after fertilization renders preimplantation embryos exceptionally hypomethylated. Here, we show that hypomethylated preimplantation mouse embryos are protected from retrotransposons by repressive histone modifications mediated by the histone chaperone chromatin assembly factor 1 (CAF-1). We found that knockdown of CAF-1 with specific siRNA injections resulted in significant up-regulation of the retrotransposons long interspersed nuclear element 1, short interspersed nuclear element B2, and intracisternal A particle at the morula stage. Concomitantly, increased histone H2AX phosphorylation and developmental arrest of the majority (>95%) of embryos were observed. The latter was caused at least in part by derepression of retrotransposons, as treatment with reverse transcriptase inhibitors rescued some embryos. Importantly, ChIP analysis revealed that CAF-1 mediated the replacement of H3.3 with H3.1/3.2 at the retrotransposon regions. This replacement was associated with deposition of repressive histone marks, including trimethylation of histone H3 on lysine 9 (H3K9me3), H3K9me2, H3K27me3, and H4K20me3. Among them, H4K20me3 and H3K9me3 seemed to play predominant roles in retrotransposon silencing, as assessed by knockdown of specific histone methyltransferases and forced expression of unmethylatable mutants of H3.1K9 and H4K20. Our data thus indicate that CAF-1 is an essential guardian of the genome in preimplantation mouse embryos by deposition of repressive histone modifications via histone variant replacement.

本文言語English
ページ(範囲)14641-14646
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
112
47
DOI
出版ステータスPublished - 2015 11 24

ASJC Scopus subject areas

  • General

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