Lehnertz Bernhard, Ueda Yoshihide, Derijck Alwin A H A, Braunschweig Ulrich, Perez-Burgos Laura, Kubicek Stefan, Chen Taiping, Li En, Jenuwein Thomas, Peters Antoine H F M
Research Institute of Molecular Pathology (IMP), The Vienna Biocenter, Dr. Bohrgasse 7, A-1030 Vienna, Austria.
Curr Biol. 2003 Jul 15;13(14):1192-200. doi: 10.1016/s0960-9822(03)00432-9.
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.
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 HP1 alpha 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.
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.
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性标志。最近研究表明，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，尚不清楚在哺乳动物中是否存在类似的依赖性。
在此，我们证明了哺乳动物中Suv39h-HP1组蛋白甲基化系统与DNA甲基转移酶3b（Dnmt3b）之间存在物理和功能联系。在野生型细胞中，Dnmt3b与HP1α相互作用并集中在异染色质位点，而在Suv39h双敲除（dn）小鼠胚胎干细胞（ES）中，它无法定位于这些区域。一致地，Suv39h dn ES细胞在着丝粒卫星重复序列处显示出改变的DNA甲基化谱，但在其他重复序列处则没有。相反，在Dnmt1单缺陷或Dnmt3a/Dnmt3b双缺陷的ES细胞中，着丝粒异染色质处的H3-K9三甲基化并未受损。我们还表明，着丝粒异染色质并非转录惰性的，并且可以产生跨越主要卫星重复序列的转录本。
这些数据证明了哺乳动物中组蛋白H3-K9甲基化和DNA甲基化之间存在进化保守的途径。虽然Suv39h组蛋白甲基转移酶是着丝粒重复序列处指导H3-K9三甲基化和Dnmt3b依赖性DNA甲基化所必需的，但着丝粒重复序列处的DNA甲基化独立于Suv39h功能而发生。因此，我们的数据还表明哺乳动物中组蛋白和DNA甲基化系统之间存在更复杂的相互关系。这两种甲基化系统可能在增强异染色质亚结构域的稳定性从而保护基因组完整性方面都很重要。
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