Cellular quiescence is a reversible differentiation state during which cells modify their gene expression program to inhibit metabolic functions and adapt to a new cellular environment. The epigenetic changes accompanying these alterations are not well understood. We used fission yeast cells as a model to study the regulation of quiescence. When these cells are starved for nitrogen, the cell cycle is arrested in G1, and the cells enter quiescence (G0). A gene regulatory program is initiated, including downregulation of thousands of genes—for example, those related to cell proliferation—and upregulation of specific genes—for example, autophagy genes—needed to adapt to the physiological challenge. These changes in gene expression are accompanied by a marked alteration of nuclear organization and chromatin structure. Here, we investigated the role of Leo1, a subunit of the conserved RNA polymerase-associated factor 1 (Paf1) complex, in the quiescence process using fission yeast as the model organism. Heterochromatic regions became very dynamic in fission yeast in G0 during nitrogen starvation. The reduction of heterochromatin in early G0 was correlated with reduced target of rapamycin complex 2 (TORC2) signaling. We demonstrated that cells lacking Leo1 show reduced survival in G0. In these cells, heterochromatic regions, including subtelomeres, were stabilized, and the expression of many genes, including membrane transport genes, was abrogated. TOR inhibition mimics the effect of nitrogen starvation, leading to the expression of subtelomeric genes, and this effect was suppressed by genetic deletion of leo1. We identified a protein, Leo1, necessary for survival during quiescence. Leo1 is part of a conserved protein complex, Paf1C, linked to RNA polymerase II. We showed that Leo1, acting downstream of TOR, is crucial for the dynamic reorganization of chromosomes and the regulation of gene expression during cellular quiescence. Genes encoding membrane transporters are not expressed in quiescent leo1 mutant cells, and cells die after 2 weeks of nitrogen starvation. Taken together, our results suggest that Leo1 is essential for the dynamic regulation of heterochromatin and gene expression during cellular quiescence.

中文翻译：

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Leo1对于细胞静止过程中异染色质和基因表达的动态调节至关重要。

细胞静止状态是可逆的分化状态，在此状态下，细胞会修改其基因表达程序以抑制代谢功能并适应新的细胞环境。伴随这些改变的表观遗传变化还不是很清楚。我们使用裂殖酵母细胞作为模型来研究静止的调节。当这些细胞因缺氮而饥饿时，细胞周期停滞在G1中，细胞进入静止状态（G0）。启动了基因调节程序，包括下调数千种基因（例如与细胞增殖有关的那些基因）和上调特定基因（例如自噬基因）以适应生理挑战。这些基因表达的变化伴随着核组织和染色质结构的显着改变。这里，我们研究了裂变酵母作为模型有机体在静止过程中Leo1（保守的RNA聚合酶相关因子1（Paf1）复合物的亚基）的作用。氮饥饿期间，G0的裂变酵母中异色区变得非常动态。G0早期异染色质的减少与雷帕霉素复合物2（TORC2）信号转导的靶标降低有关。我们证明缺少Leo1的细胞在G0中显示出降低的存活率。在这些细胞中，包括亚端粒在内的异色区域被稳定化，包括膜转运基因在内的许多基因的表达被取消。TOR抑制模拟了氮饥饿的作用，导致亚端粒基因的表达，而这种作用被leo1的基因缺失所抑制。我们鉴定出一种蛋白Leo1，静止期间生存所必需的。Leo1是保守蛋白复合物Paf1C的一部分，与RNA聚合酶II连接。我们表明，在TOR下游起作用的Leo1对染色体的动态重组和细胞静止过程中基因表达的调节至关重要。编码膜转运蛋白的基因在静止的leo1突变细胞中不表达，并且在缺氮2周后死亡。综上所述，我们的结果表明Leo1对于细胞静止过程中异染色质的动态调节和基因表达至关重要。编码膜转运蛋白的基因在静止的leo1突变细胞中不表达，并且在缺氮2周后死亡。综上所述，我们的结果表明Leo1对于细胞静止过程中异染色质的动态调节和基因表达至关重要。编码膜转运蛋白的基因在静止的leo1突变细胞中不表达，并且在缺氮2周后死亡。综上所述，我们的结果表明Leo1对于细胞静止过程中异染色质的动态调节和基因表达至关重要。