The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
Mol Cell. 2019 Aug 22;75(4):683-699.e7. doi: 10.1016/j.molcel.2019.06.034. Epub 2019 Aug 6.
Transcriptional regulation in eukaryotes occurs at promoter-proximal regions wherein transcriptionally engaged RNA polymerase II (Pol II) pauses before proceeding toward productive elongation. The role of chromatin in pausing remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6 binds to Pol II and prevents the release of the negative elongation factor (NELF), thus stabilizing Pol II promoter-proximal pausing. Genetic depletion of SIRT6 or its chromatin deficiency upon glucose deprivation causes intragenic enrichment of acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of cyclin-dependent kinase 9 (CDK9)-that phosphorylates NELF and the carboxyl terminal domain of Pol II-and enrichment of the positive transcription elongation factors MYC, BRD4, PAF1, and the super elongation factors AFF4 and ELL2. These events lead to increased expression of genes involved in metabolism, protein synthesis, and embryonic development. Our results identified SIRT6 as a Pol II promoter-proximal pausing-dedicated histone deacetylase.
真核生物中的转录调控发生在启动子近端区域，其中转录活跃的 RNA 聚合酶 II（Pol II）在进行有效的延伸之前会暂停。染色质在暂停中的作用仍知之甚少。在这里，我们证明了组蛋白去乙酰化酶 SIRT6 与 Pol II 结合，并阻止负延伸因子（NELF）的释放，从而稳定 Pol II 启动子近端暂停。葡萄糖剥夺时 SIRT6 的遗传耗竭或其染色质缺陷会导致组蛋白 H3 在赖氨酸 9（H3K9ac）和 56（H3K56ac）处乙酰化的基因内富集，周期蛋白依赖性激酶 9（CDK9）的激活 - 磷酸化 NELF 和 Pol II 的羧基末端结构域 - 和正转录延伸因子 MYC、BRD4、PAF1 以及超延伸因子 AFF4 和 ELL2 的富集。这些事件导致参与代谢、蛋白质合成和胚胎发育的基因表达增加。我们的结果确定 SIRT6 为 Pol II 启动子近端暂停专用组蛋白去乙酰化酶。
