Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development

Ye Guang Hu, Ryutaro Hirasawa, Jia Lei Hu, Kenichiro Hata, Chun Liang Li, Ying Jin, Taiping Chen, En Li, Muriel Rigolet, Evani Viegas-Péquignot, Hiroyuki Sasaki, Guo Liang Xu

研究成果: Contribution to journalArticle査読

49 被引用数 (Scopus)

抄録

The genomic DNA is methylated by de novo methyltransferases Dnmt3a and Dnmt3b during early embryonic development. The establishment of appropriate methylation patterns depends on a fine regulation of the methyltransferase activity. The activity of both enzymes increases in the presence of Dnmt3L, a Dnmt3a/3b-like protein. However, it is unclear how the function of Dnmt3L is regulated. We found here that the expression of Dnmt3L is controlled via its promoter methylation during embryonic development. Genetic studies showed that Dnmt3a, Dnmt3b and Dnmt3L are all involved in the methylation of the Dnmt3L promoter. Disruption of both Dnmt3a and Dnmt3b genes in mouse rendered the Dnmt3L promoter devoid of methylation, causing incomplete repression of the Dnmt3L transcription in embryonic stem cells and embryos. Disruption of either Dnmt3a or Dnmt3b led to reduced methylation and increased transcription of Dnmt3L, but severe hypomethylation occurred only when Dnmt3b was deficient. Consistent with the major contribution of Dnmt3b in the Dnmt3L promoter methylation, methylation of Dnmt3L was significantly reduced in mouse models of the human ICF syndrome carrying point mutations in Dnmt3b. Interestingly, Dnmt3L also contributes to the methylation of its own promoter in embryonic development. We thus propose an auto-regulatory mechanism for the control of DNA methylation activity whereby the activity of the Dnmt3L promoter is epigenetically modulated by the methylation machinery including Dnmt3L itself. Insufficient methylation of the DNMT3L promoter during embryonic development due to deficiency in DNMT3B might be implicated in the pathogenesis of the ICF syndrome.

本文言語英語
ページ(範囲)2654-2664
ページ数11
ジャーナルHuman molecular genetics
17
17
DOI
出版ステータス出版済み - 2008
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)

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