Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development
Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development
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胚胎发育过程中 Dnmt3 酶通过 Dnmt3L 启动子甲基化调节 DNA 甲基化活性
DOI：
10.1093/hmg/ddn165
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
Xu, Guo-Liang
中科院分区：
文献类型：
--
作者：
Hu, Ye-Guang;Hirasawa, Ryutaro;Xu, Guo-Liang
基因组DNA在早期胚胎发育过程中被从头甲基转移酶Dnmt 3a和Dnmt 3b甲基化。适当的甲基化模式的建立依赖于甲基转移酶活性的精细调节。这两种酶的活性在Dnmt 3L（一种Dnmt 3a/3b样蛋白）存在下增加。然而，目前还不清楚Dnmt 3L的功能是如何调节的。我们发现在胚胎发育过程中，Dnmt 3L的表达是通过其启动子甲基化来控制的。遗传学研究表明，Dnmt 3a、Dnmt 3b和Dnmt 3L都参与了Dnmt 3L启动子的甲基化。小鼠中Dnmt 3a和Dnmt 3b基因的破坏使得Dnmt 3L启动子缺乏甲基化，导致胚胎干细胞和胚胎中Dnmt 3L转录的不完全抑制。Dnmt 3a或Dnmt 3b的破坏导致Dnmt 3L的甲基化减少和转录增加，但只有当Dnmt 3b缺陷时才发生严重的低甲基化。与Dnmt 3b在Dnmt 3L启动子甲基化中的主要贡献一致，在携带Dnmt 3b点突变的人ICF综合征小鼠模型中，Dnmt 3L的甲基化显著降低。有趣的是，Dnmt 3L也有助于胚胎发育中自身启动子的甲基化。因此，我们提出了一种自动调节机制，用于控制DNA甲基化活性，其中Dnmt 3L启动子的活性由包括Dnmt 3L本身的甲基化机制表观遗传地调节。在胚胎发育过程中，由于DNMT 3B缺陷，DNMT 3L启动子甲基化不足可能与ICF综合征的发病机制有关。
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.