Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation
Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation
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DOI：
10.1038/70602
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发表时间：
1999-12-01
期刊：
影响因子：
30.8
通讯作者：
Otte, AP
中科院分区：
文献类型：
--
作者：
van der Vlag, J;Otte, AP
多梳组（PcG）蛋白形成多聚体蛋白复合物，其参与在连续的细胞世代中维持基因的转录抑制状态（1-3）。通过广泛的遗传和生物化学分析，已经鉴定和分析了PcG复合物的组分及其相互作用。然而，PcG介导的基因活性抑制的分子机制在很大程度上仍然未知。以前，我们报道了两种不同的人PcG蛋白复合物的存在（4）。EED/EZH蛋白复合物含有胚胎外胚层发育（4-8）（EED）和zeste 2增强子（EZH 2;参考文献9、10）PcG蛋白。HPC/HPH PcG复合物含有人polycomb 2（HPC 2;参考文献11）、人polyhomeotic（12）（HPH）、BMI 1（参考文献13）和RING 1（参考文献14、15）蛋白。在这里，我们表明EED（参考文献4-8）在体外和体内与组蛋白脱乙酰酶（HDAC）蛋白相互作用（16，17）。这种相互作用是高度特异性的，因为HDAC蛋白不与其他脊椎动物PcG蛋白相互作用。我们进一步发现组蛋白去乙酰化活性与EED蛋白共免疫沉淀。最后，组蛋白去乙酰化酶抑制剂利司他汀A（参考文献17）可缓解EED介导的转录抑制，但不能缓解多梳的人类同源物HPC 2介导的转录抑制（11）。我们的数据表明，PcG介导的基因活性抑制涉及组蛋白去乙酰化。两个不同的全球基因抑制系统之间的这种机制联系是通过HDAC蛋白与特定PcG蛋白（EED）的相互作用实现的。
Polycomb-group (PcG) proteins form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations(1-3) Components of PcG complexes and their mutual interactions have been identified and analysed through extensive genetic and biochemical analyses. Molecular mechanisms underlying PcG-mediated repression of gene activity, however, have remained largely unknown. Previously we reported the existence of two distinct human PcG protein complexes(4). The EED/EZH protein complex contains the embryonic ectoderm development(4-8) (EED) and enhancer of zeste 2 (EZH2; refs 9,10) PcG proteins. The HPC/HPH PcG complex contains the human polycomb 2 (HPC2; ref. 11), human polyhomeotic(12) (HPH), BMI1 (ref. 13) and RING1 (refs 14,15) proteins. Here we show that EED (refs 4-8) interacts, both in vitro and in vivo, with histone deacetylase (HDAC) proteins(16,17). This interaction is highly specific because the HDAC proteins do not interact with other vertebrate PcG proteins. We further find that histone deacetylation activity co-immunoprecipitates with the EED protein. Finally, the histone deacetylase inhibitor trichostatin A (ref. 17) relieves transcriptional repression mediated by EED, but not by HPC2, a human homologue of polycomb(11). Our data indicate that PcG-mediated repression of gene activity involves histone deacetylation. This mechanistic link between two distinct, global gene repression systems is accomplished through the interaction of HDAC proteins with a particular PcG protein, EED.