Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin
Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin
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DOI：
10.1016/s0960-9822(03)00432-9
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发表时间：
2003-07-15
期刊：
影响因子：
9.2
通讯作者：
Peters, AHFM
中科院分区：
文献类型：
--
作者：
Lehnertz, B;Ueda, Y;Peters, AHFM
背景：组蛋白 H3 赖氨酸 9 (H3-K9) 甲基化和 DNA 甲基化是哺乳动物异染色质的特征标志。最近显示 H3-K9 甲基化是粗糙脉孢菌和拟南芥中 DNA 甲基化的先决条件。目前，尚不清楚哺乳动物中是否存在类似的依赖性。结果：在这里，我们证明了哺乳动物中 Suv39h-HP1 组蛋白甲基化系统和 DNA 甲基转移酶 3b (Dnmt3b) 之间的物理和功能联系。尽管在野生型细胞中，Dnmt3b 与 HP1α 相互作用并集中在异染色质灶上，但在 Suv39h 双无效 (dn) 小鼠胚胎干 (ES) 细胞中，它无法定位到这些区域。一致的是，Suv39h dn ES 细胞在中心卫星重复序列中显示出改变的 DNA 甲基化谱，但在其他重复序列中则没有。相比之下，在 Dnmt1 单缺陷或 Dnmt3a/Dnmt3b 双缺陷 ES 细胞中，中心周围异染色质的 H3-K9 三甲基化并未受损。我们还表明，中心周异染色质不是转录惰性的，并且可以产生跨越主要卫星重复序列的转录本。结论：这些数据表明哺乳动物中组蛋白 H3-K9 甲基化和 DNA 甲基化之间存在进化保守的途径。虽然 Suv39h HMTase 需要在着丝粒重复序列中指导 H3-K9 三甲基化和 Dnmt3b 依赖性 DNA 甲基化，但着丝粒重复序列的 DNA 甲基化发生独立于 Suv39h 功能。因此，我们的数据还表明哺乳动物组蛋白和 DNA 甲基化系统之间存在更复杂的相互关系。两种甲基化系统可能对于增强异染色质亚结构域的稳定性并从而保护基因组完整性很重要。
Background: Histone H3 lysine 9 (H3-K9) methylation and DNA methylation are characteristic hallmarks of mammalian heterochromatin. H3-K9 methylation was recently shown to be a prerequisite for DNA methylation in Neurospora crassa and Arabidopsis thaliana. Currently, it is unknown whether a similar dependence exists in mammalian organisms.Results: Here, we demonstrate a physical and functional link between the Suv39h-HP1 histone methylation system and DNA methyltransferase 3b (Dnmt3b) in mammals. Whereas in wild-type cells Dnmt3b interacts with HP1alpha and is concentrated at heterochromatic foci, it fails to localize to these regions in Suv39h double null (dn) mouse embryonic stem (ES) cells. Consistently, the Suv39h dn ES cells display an altered DNA methylation profile at pericentric satellite repeats, but not at other repeat sequences. In contrast, H3-K9 trimethylation at pericentric heterochromatin is not impaired in Dnmt1 single- or Dnmt3a/Dnmt3b double-deficient ES cells. We also show that pericentric heterochromatin is not transcriptionally inert and can give rise to transcripts spanning the major satellite repeats.Conclusions: These data demonstrate an evolutionarily conserved pathway between histone H3-K9 methylation and DNA methylation in mammals. While the Suv39h HMTases are required to direct H3-K9 trimethylation and Dnmt3b-dependent DNA methylation at pericentric repeats, DNA methylation at centromeric repeats occurs independent of Suv39h function. Thus, our data also indicate a more complex interrelatedness between histone and DNA methylation systems in mammals. Both methylation systems are likely to be important in reinforcing the stability of heterochromatic subdomains and thereby in protecting genome integrity.