Yamada Takatomi, Fischle Wolfgang, Sugiyama Tomoyasu, Allis C David, Grewal Shiv I S
Laboratory of Molecular Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Cell. 2005 Oct 28;20(2):173-85. doi: 10.1016/j.molcel.2005.10.002.
Posttranslational modifications of histones play an essential role in heterochromatin assembly. Whereas the role of Clr4/Suv39h-mediated methylation of histone H3 at lysine 9 (H3K9) in heterochromatin assembly is well studied, the exact function of histone deacetylases (HDACs) in this process is unclear. We show that Clr3, a fission yeast homolog of mammalian class II HDACs, acts in a distinct pathway parallel to RNAi-directed heterochromatin nucleation to recruit Clr4 and mediate H3K9 methylation at the silent mating-type region and centromeres. At the mat locus, Clr3 is recruited at a specific site through a mechanism involving ATF/CREB family proteins. Once recruited, Clr3 spreads across the 20 kb silenced domain that requires its own HDAC activity and heterochromatin proteins including Swi6/HP1. We also demonstrate that Clr3 contributes to heterochromatin maintenance by stabilizing H3K9 trimethylation and by preventing histone modifications associated with active transcription, and that it limits RNA polymerase II accessibility to naturally silenced repeats at heterochromatin domains.
组蛋白的翻译后修饰在异染色质组装中起着至关重要的作用。虽然Clr4/Suv39h介导的组蛋白H3赖氨酸9（H3K9）甲基化在异染色质组装中的作用已得到充分研究，但组蛋白去乙酰化酶（HDACs）在此过程中的具体功能尚不清楚。我们发现，裂殖酵母中与哺乳动物II类HDACs同源的Clr3，在一条与RNAi介导的异染色质成核平行的独特途径中发挥作用，以招募Clr4并介导沉默交配型区域和着丝粒处的H3K9甲基化。在交配型位点，Clr3通过一种涉及ATF/CREB家族蛋白的机制被招募到一个特定位点。一旦被招募，Clr3会扩散到20 kb的沉默结构域，这需要其自身的HDAC活性以及包括Swi6/HP1在内的异染色质蛋白。我们还证明，Clr3通过稳定H3K9三甲基化和防止与活跃转录相关的组蛋白修饰来促进异染色质的维持，并且它限制了RNA聚合酶II接近异染色质结构域中天然沉默的重复序列。
