Yamamoto Ken, Sonoda Miki, Inokuchi Junichi, Shirasawa Senji, Sasazuki Takehiko
Division of Molecular Population Genetics, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
J Biol Chem. 2004 Jan 2;279(1):401-6. doi: 10.1074/jbc.M307344200. Epub 2003 Oct 21.
Drosophila suppressor of zeste 12 (Su(z)12) is a Polycomb group (PcG) transcriptional repressor and is present in E(z)-ESC, a multiprotein complex with methylation activity specific for lysine 9 and 27 of histone H3. Although PcG- and heterochromatin-mediated gene silencing have been considered distinct, mutant flies of Su(z)12 showed not only homeotic transformation but also position effect variegation. We now report that the mammalian SU(Z)12 directly interacts with heterochromatin protein 1alpha (HP1alpha) and PcG enhancer of zeste 2 (EZH2), the mammalian counterpart of E(z), in vitro and in vivo. Two distinct domains in SU(Z)12 are involved in these interactions, the region between the zinc finger motif and the VEFS (VRN2-EMF2-FIS2-Su(z)12) box for HP1alpha (amino acid residues 479-536) and the VEFS box for EZH2 (amino acid residues 600-639), which are not mutually exclusive. Interestingly this region of the VEFS box has been shown to be critical for the phenotype of the Su(z)12 mutant fly. In addition SU(Z)12 represses transcription activity in the presence of HP1alpha in a reporter assay. These results provide a molecular explanation for the functional link of these epigenetic silencing processes mediated by Su(z)12.
果蝇zeste 12抑制因子（Su(z)12）是一种多梳蛋白家族（PcG）转录抑制因子，存在于E(z)-ESC中，E(z)-ESC是一种多蛋白复合物，对组蛋白H3赖氨酸9和27具有特异性甲基化活性。尽管PcG和异染色质介导的基因沉默被认为是不同的，但Su(z)12突变果蝇不仅表现出同源异型转化，还表现出位置效应斑驳。我们现在报告，哺乳动物的SU(Z)12在体外和体内直接与异染色质蛋白1α（HP1α）以及E(z)的哺乳动物对应物zeste 2增强子（EZH2）相互作用。SU(Z)12中的两个不同结构域参与了这些相互作用，对于HP1α而言，是锌指基序和VEFS（VRN2-EMF2-FIS2-Su(z)12）框之间的区域（氨基酸残基479-536），对于EZH2而言，是VEFS框（氨基酸残基600-639），这两个区域并非相互排斥。有趣的是，VEFS框的这个区域已被证明对Su(z)12突变果蝇的表型至关重要。此外，在报告基因检测中，SU(Z)12在有HP1α存在的情况下会抑制转录活性。这些结果为Su(z)12介导的这些表观遗传沉默过程的功能联系提供了分子解释。
