A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/arf locus through polycomb repressive complex 1.
A novel zinc finger protein Zfp277 mediates transcriptional repression of the Ink4a/arf locus through polycomb repressive complex 1.
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DOI：
10.1371/journal.pone.0012373
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发表时间：
2010-08-24
期刊：
影响因子：
3.7
通讯作者：
Iwama A
中科院分区：
文献类型：
--
作者：
Negishi M;Saraya A;Mochizuki S;Helin K;Koseki H;Iwama A
Polycomb group （PcG）蛋白作为Ink4a/Arf肿瘤抑制基因位点的关键转录调控因子，在细胞衰老过程中起着至关重要的作用。然而，PcG复合物如何靶向并促进Ink4a/Arf位点的稳定基因沉默仍然知之甚少。我们检测了锌指结构域蛋白277 （Zfp277）的功能，这是一种与PcG蛋白Bmi1相互作用的新型锌指蛋白。Zfp277以不依赖于Bmi1的方式结合到Ink4a/Arf位点，并通过与Bmi1的直接作用与polycomb repressor complex (PRC) 1相互作用。小鼠胚胎成纤维细胞（mef）中Zfp277的缺失导致PcG蛋白与Ink4a/Arf位点分离，导致与p16Ink4a和p19Arf表达降低相关的过早衰老。在衰老mef中，Zfp277和PcG蛋白的水平与活性氧（ROS）的水平呈负相关，但用抗氧化剂处理Zfp277−/−mef恢复了PRC2而不是PRC1与Ink4a/Arf位点的结合。值得注意的是，在Zfp277−/−mef中强制表达Bmi1并不能恢复Bmi1与Ink4a/Arf位点的结合，也不能绕过细胞衰老。不能结合Bmi1的Zfp277突变体不能使Zfp277−/−MEFs免于过早衰老。我们的研究结果表明Zfp277参与了Ink4a/Arf基因座的转录调控，并表明Zfp277与Bmi1的相互作用对于PRC1募集到Ink4a/Arf基因座至关重要。我们的研究结果还强调了氧化应激途径对Zfp277和PcG蛋白的动态调节。
Polycomb group (PcG) proteins play a crucial role in cellular senescence as key transcriptional regulators of the Ink4a/Arf tumor suppressor gene locus. However, how PcG complexes target and contribute to stable gene silencing of the Ink4a/Arf locus remains little understood. We examined the function of Zinc finger domain-containing protein 277 (Zfp277), a novel zinc finger protein that interacts with the PcG protein Bmi1. Zfp277 binds to the Ink4a/Arf locus in a Bmi1-independent manner and interacts with polycomb repressor complex (PRC) 1 through direct interaction with Bmi1. Loss of Zfp277 in mouse embryonic fibroblasts (MEFs) caused dissociation of PcG proteins from the Ink4a/Arf locus, resulting in premature senescence associated with derepressed p16Ink4a and p19Arf expression. Levels of both Zfp277 and PcG proteins inversely correlated with those of reactive oxygen species (ROS) in senescing MEFs, but the treatment of Zfp277 −/− MEFs with an antioxidant restored the binding of PRC2 but not PRC1 to the Ink4a/Arf locus. Notably, forced expression of Bmi1 in Zfp277 −/− MEFs did not restore the binding of Bmi1 to the Ink4a/Arf locus and failed to bypass cellular senescence. A Zfp277 mutant that could not bind Bmi1 did not rescue Zfp277 −/− MEFs from premature senescence. Our findings implicate Zfp277 in the transcriptional regulation of the Ink4a/Arf locus and suggest that the interaction of Zfp277 with Bmi1 is essential for the recruitment of PRC1 to the Ink4a/Arf locus. Our findings also highlight dynamic regulation of both Zfp277 and PcG proteins by the oxidative stress pathways.
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