The cAMP signaling pathway regulates Epe1 protein levels and heterochromatin assembly.
The cAMP signaling pathway regulates Epe1 protein levels and heterochromatin assembly.
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DOI：
10.1371/journal.pgen.1010049
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发表时间：
2022-03
期刊：
影响因子：
4.5
通讯作者：
Jia S
中科院分区：
文献类型：
--
作者：
Bao K;Shan CM;Chen X;Raiymbek G;Monroe JG;Fang Y;Toda T;Koutmou KS;Ragunathan K;Lu C;Berchowitz LE;Jia S
细胞的表观遗传景观经常随着营养水平的波动而变化，但其机制联系尚不清楚。在裂变酵母中，JmjC结构域蛋白Epe1对于维持异染色质景观至关重要。虽然Epe1的缺失导致异染色质扩张，但过表达Epe1会导致异染色质缺陷。通过基因筛选，我们发现cAMP信号通路基因突变抑制与Epe1过表达相关的异染色质缺陷。我们进一步证明，激活cAMP信号传导的下游效应因子Pka1是有效翻译epe1+ mRNA以维持epe1过表达所必需的。此外，camp信号通路的失活，无论是通过基因突变还是葡萄糖剥夺，都会导致内源性Epe1的减少和相应的异染色质变化。这些结果揭示了cAMP信号通路调控裂变酵母异染色质景观的机制。基因组DNA与组蛋白折叠成染色质，组蛋白的翻译后修饰将染色质分离成活性的常染色质和抑制性的异染色质。这些染色质结构域通常会随着环境因素（如营养水平）的变化而变化。环境变化如何影响组蛋白修饰尚不清楚。在这里，我们发现在裂变酵母中，cAMP信号通路是Epe1功能所必需的，Epe1是一种去除与异染色质相关的组蛋白修饰的酶。此外，我们发现活跃的cAMP信号传导确保了epe1+ mRNA的有效翻译，从而维持了较高的epe1蛋白水平。最后，我们发现葡萄糖水平的改变，可以调节cAMP信号传导，也会以与cAMP信号传导介导的Epe1蛋白水平变化一致的方式影响异染色质。由于组蛋白修饰酶通常需要作为代谢中间体的辅助因子，以往关于营养水平对染色质状态影响的研究主要集中在代谢物上。我们的研究结果表明，营养感应信号通路也调节组蛋白修饰酶，以响应营养条件。
The epigenetic landscape of a cell frequently changes in response to fluctuations in nutrient levels, but the mechanistic link is not well understood. In fission yeast, the JmjC domain protein Epe1 is critical for maintaining the heterochromatin landscape. While loss of Epe1 results in heterochromatin expansion, overexpression of Epe1 leads to defective heterochromatin. Through a genetic screen, we found that mutations in genes of the cAMP signaling pathway suppress the heterochromatin defects associated with Epe1 overexpression. We further demonstrated that the activation of Pka1, the downstream effector of cAMP signaling, is required for the efficient translation of epe1+ mRNA to maintain Epe1 overexpression. Moreover, inactivation of the cAMP-signaling pathway, either through genetic mutations or glucose deprivation, leads to the reduction of endogenous Epe1 and corresponding heterochromatin changes. These results reveal the mechanism by which the cAMP signaling pathway regulates heterochromatin landscape in fission yeast. Genomic DNA is folded with histones into chromatin and posttranslational modifications on histones separate chromatin into active euchromatin and repressive heterochromatin. These chromatin domains often change in response to environmental cues, such as nutrient levels. How environmental changes affect histone modifications is not well understood. Here, we found that in fission yeast, the cAMP signaling pathway is required for the function of Epe1, an enzyme that removes histone modifications associated with heterochromatin. Moreover, we found that active cAMP signaling ensures the efficient translation of epe1+ mRNA and therefore maintains high Epe1 protein levels. Finally, we show that changing glucose levels, which modulate cAMP signaling, also affect heterochromatin in a way consistent with cAMP signaling-mediated Epe1 protein level changes. As histone-modifying enzymes often require cofactors that are metabolic intermediates, previous studies on the impact of nutrient levels on chromatin states have mainly focused on metabolites. Our results suggest that nutrient-sensing signaling pathways also regulate histone-modifying enzymes in response to nutritional conditions.
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DOI：
10.1146/annurev-cellbio-100814-125544
发表时间：
2015
影响因子：
11.3
作者：
Janke R;Dodson AE;Rine J
通讯作者：
Rine J
影响因子：
4.8
作者：
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影响因子：
56.9
作者：
Nakayam, J;Rice, JC;Grewal, SIS
通讯作者：
Grewal, SIS
影响因子：
64.5
作者：
Braun S;Garcia JF;Rowley M;Rougemaille M;Shankar S;Madhani HD
通讯作者：
Madhani HD
影响因子：
56.9
作者：
Jia, ST;Noma, K;Grewal, SIS
通讯作者：
Grewal, SIS