Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription.
Phosphorylation of histone H3 serine 28 modulates RNA polymerase III-dependent transcription.
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DOI：
10.1038/onc.2011.105
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发表时间：
2011-09-15
期刊：
影响因子：
8
通讯作者：
Zhong S
中科院分区：
文献类型：
--
作者：
Zhang Q;Zhong Q;Evans AG;Levy D;Zhong S
RNA 聚合酶 III (Pol III) 转录的失调会增强细胞 tRNA 和 5S rRNA 的产生，导致翻译能力增加，从而促进细胞增殖、转化和肿瘤形成。组蛋白 H3 (H3ph) 的磷酸化由肿瘤启动子（EGF、UV 和 TPA）和立即早期基因（例如 c-myc、c-jun 和 c-fos）诱导。然而，H3ph 是否参与 RNA Pol III 转录仍有待确定。在这里，我们报告 EGF 在丝氨酸 28 (H3S28ph) 处强烈诱导 H3ph。 EGF 显着增加 RNA Pol III 依赖性基因（Pol III 基因）、tRNALeu、tRNATyr、5S rRNA 和 7SL RNA 的转录。抑制 EGFR（而非 PI3K）会减少 H3S28ph、tRNALeu 和 5S rRNA 转录。 EGF 增强了 tRNALeu 和 5S rRNA 启动子中 H3S28ph 的占据。进一步分析表明，EGF 增加了 TFIIIB 亚基、Brf1 和 TBP 的蛋白质和 mRNA 的细胞水平。 Brf1 是 RNA Pol III 基因的特异性转录因子。 EGF 增强了 Brf1 和 TBP 启动子中 H3S28ph 的占据。突变体 H3S28A 对 H3S28ph 的抑制抑制了 Brf1、TBP 和 tRNALeu 以及 5S rRNA 的表达，并减少了 H3S28ph 在其启动子中的占据。 Brf1 的减少显着降低了 tRNALeu 和 5S rRNA 转录并抑制 EGF 诱导的锚定非依赖性生长。使用突变体 H3S28A 阻断 H3S28ph 信号传导可减少 EGF 诱导的细胞转化。总之，这些结果表明 EGF 激活 EGFR 信号转导诱导 H3S28ph，进而通过 Brf1 和 TBP 上调 tRNALeu 和 5S rRNA 转录并促进细胞转化。研究表明，H3S28ph 的表观遗传修饰在 Pol III 基因的活性中起着至关重要的作用。
Deregulation of RNA polymerase III (Pol III) transcription enhances cellular tRNAs and 5S rRNA production, leading to an increase in translational capacity to promote cell proliferation, transformation and tumor formation. Phosphorylation of histone H3 (H3ph) is induced by tumor promoters (EGF, UV and TPA) and immediate early genes, such as c-myc, c-jun and c-fos. However, it remains to be determined whether H3ph is involved in RNA Pol III transcription. Here, we report that EGF strongly induced H3ph at serine 28 (H3S28ph). EGF significantly increased transcription of RNA Pol III-dependent genes (Pol III genes), tRNALeu, tRNATyr, 5S rRNA, and 7SL RNA. Inhibition of EGFR, but not PI3K, reduced both H3S28ph and tRNALeu and 5S rRNA transcription. EGF enhanced occupancy of H3S28ph in the promoters of tRNALeu and 5S rRNA. Further analysis indicates that EGF augmented cellular levels of protein and mRNA of TFIIIB subunits, Brf1 and TBP. Brf1 is a specific transcription factor for RNA Pol III genes. EGF enhanced occupancy of H3S28ph in the Brf1 and TBP promoters. Inhibition of H3S28ph by mutant H3S28A repressed Brf1, TBP and tRNALeu and 5S rRNA expression and decreased occupancy of H3S28ph in their promoters. Reduction of Brf1 significantly decreased tRNALeu and 5S rRNA transcription and repressed EGF-induced anchorage-independent growth. Blocking H3S28ph signaling by using mutant H3S28A reduced EGF-induced cell transformation. Together, these results indicate that EGF activates EGFR signaling to induce H3S28ph, which, in turn, upregulates tRNALeu and 5S rRNA transcription through Brf1 and TBP and promotes cell transformation. The studies demonstrate that epigenetic modification of H3S28ph plays a critical role in the activity of Pol III genes.