SETDB1 is involved in postembryonic DNA methylation and gene silencing in Drosophila.
SETDB1 is involved in postembryonic DNA methylation and gene silencing in Drosophila.
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DOI：
10.1371/journal.pone.0010581
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发表时间：
2010-05-17
期刊：
影响因子：
3.7
通讯作者：
Sauer F
中科院分区：
文献类型：
--
作者：
Gou D;Rubalcava M;Sauer S;Mora-Bermúdez F;Erdjument-Bromage H;Tempst P;Kremmer E;Sauer F
DNA甲基化是基因组稳定性和活性的基础。果蝇和脊椎动物在早期胚胎发生过程中建立了基因组的整体DNA甲基化模式。对DNA甲基化模式的大规模分析揭示了DNA甲基化模式是动态的而不是静态的，并且在发育过程中和病变细胞中以基因特异性的方式变化。然而，涉及动态的胚后DNA甲基化的因素和机制仍不清楚。组蛋白甲基转移酶（HMTs）的Su（var）3-9家族成员甲基化组蛋白H3（H3-K9）中的赖氨酸9触发节肢动物和脊索动物中的胚胎DNA甲基化。在这里，我们证明果蝇SETDB 1（dSETDB 1）可以介导DNA甲基化和基因和反转录转座子的沉默。我们发现dSETDB 1三甲基化H3-K9并结合甲基化的CpA基序。H3-K9通过dSETDB 1的三甲基化介导DNA甲基转移酶2（Dnmt 2）和Su（var）205（哺乳动物“异染色质蛋白1”的果蝇直系同源物）募集到dSETDB 1的靶基因。dSETDB 1通过激活Dnmt 2和Su（var）205，触发果蝇细胞中基因和反转录转座子的DNA甲基化和沉默。DSETDB 1参与胚后DNA甲基化和Rt 1b {}反转录转座子和肿瘤抑制基因视网膜母细胞瘤家族蛋白1（Rb）在胚盘中的沉默。总的来说，我们的研究结果涉及dSETDB 1在胚后DNA甲基化，提供了一个模型，沉默的肿瘤抑制基因Rb，并揭示了细胞类型特异性DNA甲基化在果蝇发育中的作用。
DNA methylation is fundamental for the stability and activity of genomes. Drosophila melanogaster and vertebrates establish a global DNA methylation pattern of their genome during early embryogenesis. Large-scale analyses of DNA methylation patterns have uncovered revealed that DNA methylation patterns are dynamic rather than static and change in a gene-specific fashion during development and in diseased cells. However, the factors and mechanisms involved in dynamic, postembryonic DNA methylation remain unclear. Methylation of lysine 9 in histone H3 (H3-K9) by members of the Su(var)3–9 family of histone methyltransferases (HMTs) triggers embryonic DNA methylation in Arthropods and Chordates. Here, we demonstrate that Drosophila SETDB1 (dSETDB1) can mediate DNA methylation and silencing of genes and retrotransposons. We found that dSETDB1 tri-methylates H3-K9 and binds methylated CpA motifs. Tri-methylation of H3-K9 by dSETDB1 mediates recruitment of DNA methyltransferase 2 (Dnmt2) and Su(var)205, the Drosophila ortholog of mammalian “Heterochromatin Protein 1”, to target genes for dSETDB1. By enlisting Dnmt2 and Su(var)205, dSETDB1 triggers DNA methylation and silencing of genes and retrotransposons in Drosophila cells. DSETDB1 is involved in postembryonic DNA methylation and silencing of Rt1b{} retrotransposons and the tumor suppressor gene retinoblastoma family protein 1 (Rb) in imaginal discs. Collectively, our findings implicate dSETDB1 in postembryonic DNA methylation, provide a model for silencing of the tumor suppressor Rb, and uncover a role for cell type-specific DNA methylation in Drosophila development.
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