Leo1 is essential for the dynamic regulation of heterochromatin and gene expression during cellular quiescence
Leo1 is essential for the dynamic regulation of heterochromatin and gene expression during cellular quiescence
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DOI：
10.1186/s13072-019-0292-7
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发表时间：
2019-07-17
影响因子：
3.9
通讯作者：
Ekwall, Karl
中科院分区：
文献类型：
--
作者：
Oya, Eriko;Durand-Dubief, Mickael;Ekwall, Karl
背景资料：细胞静止是一种可逆的分化状态，在此期间细胞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清楚。我们使用分裂酵母细胞作为模型来研究静止的调节。当这些细胞缺乏氮时，细胞周期停滞在G1期，细胞进入静止期（G0）。启动基因调控程序，包括下调数千个基因（例如，与细胞增殖相关的基因）和上调适应生理挑战所需的特定基因（例如，自噬基因）。这些基因表达的变化是伴随着一个显着的核组织和染色质structure.Results的改变：在这里，我们调查的作用Leo1，保守的RNA聚合酶相关因子1（Paf1）复合物的亚基，在静止过程中使用裂殖酵母作为模式生物。异染色质区域在G0期的分裂酵母中变得非常活跃。G0早期异染色质的减少与雷帕霉素复合物2（TORC 2）信号转导的靶点减少相关。我们证明了缺乏Leo1的细胞在G0期的存活率降低。在这些细胞中，异染色质区域，包括亚端粒，被稳定，许多基因的表达，包括膜转运基因，被废除。TOR抑制模拟氮饥饿的作用，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。结论：我们鉴定了一种在静止期生存所必需的蛋白Leo1。Leo1是一种保守的蛋白质复合物Paf1C的一部分，与RNA聚合酶II相连。我们发现，Leo 1，TOR的下游，是至关重要的动态重组染色体和基因表达的调控细胞静止期。编码膜转运蛋白的基因在静止的leo1突变体细胞中不表达，细胞在氮饥饿2周后死亡。两者合计，我们的研究结果表明，利奥1是必不可少的异染色质和基因表达的动态调节细胞静止期。
Background: 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.Results: 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.Conclusions: 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.