Department of Pathology and Laboratory Medicine and Center for Adult Cancer Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Nucleic Acids Res. 2012 Aug;40(14):6534-46. doi: 10.1093/nar/gks345. Epub 2012 May 2.
Epigenetic changes in chromatin through histone post-translational modifications are essential for altering gene transcription in response to environmental cues. How histone modifications are regulated by environmental stimuli remains poorly understood yet this process is critical for delineating how epigenetic pathways are influenced by the cellular environment. We have used the target of rapamycin (TOR) pathway, which transmits environmental nutrient signals to control cell growth, as a model to delineate mechanisms underlying this phenomenon. A chemical genomics screen using the TOR inhibitor rapamycin against a histone H3/H4 mutant library identified histone H3 lysine 56 acetylation (H3K56ac) as a chromatin modification regulated by TOR signaling. We demonstrate this acetylation pathway functions in TOR-dependent cell growth in part by contributing directly to ribosomal RNA (rRNA) biogenesis. Specifically, H3K56ac creates a chromatin environment permissive to RNA polymerase I transcription and nascent rRNA processing by regulating binding of the high mobility group protein Hmo1 and the small ribosomal subunit (SSU) processome complex. Overall, these studies identify a novel chromatin regulatory role for TOR signaling and support a specific function for H3K56ac in ribosomal DNA (rDNA) gene transcription and nascent rRNA processing essential for cell growth.
染色质组蛋白翻译后修饰导致的表观遗传改变对于基因转录在环境刺激下的改变至关重要。然而，组蛋白修饰如何受到环境刺激的调控仍知之甚少，而这一过程对于阐明表观遗传途径如何受到细胞环境的影响至关重要。我们使用雷帕霉素（TOR）通路作为模型，该通路传递环境营养信号以控制细胞生长，来阐明这一现象的潜在机制。利用 TOR 抑制剂雷帕霉素对组蛋白 H3/H4 突变文库进行的化学基因组筛选，确定了组蛋白 H3 赖氨酸 56 乙酰化（H3K56ac）是受 TOR 信号调控的染色质修饰。我们证明，该乙酰化途径在 TOR 依赖性细胞生长中发挥作用，部分原因是其直接参与核糖体 RNA（rRNA）的生物发生。具体而言，H3K56ac 通过调节高迁移率族蛋白 Hmo1 和小核糖体亚基（SSU）加工体复合物的结合，创建允许 RNA 聚合酶 I 转录和新生 rRNA 加工的染色质环境。总的来说，这些研究确定了 TOR 信号的一种新的染色质调控作用，并支持 H3K56ac 在核糖体 DNA（rDNA）基因转录和新生 rRNA 加工中的特定功能，这对于细胞生长是必不可少的。
