Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences.
Amino acid deprivation triggers a novel GCN2-independent response leading to the transcriptional reactivation of non-native DNA sequences.
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DOI：
10.1371/journal.pone.0200783
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Schiaffino MV
中科院分区：
文献类型：
--
作者：
De Vito A;Lazzaro M;Palmisano I;Cittaro D;Riba M;Lazarevic D;Bannai M;Gabellini D;Schiaffino MV
在许多物种中，减少食物摄入，特别是蛋白质或氨基酸（AA）的限制，延长寿命和健康。然而，潜在的表观遗传和/或转录机制在很大程度上是未知的，解剖培养细胞中的特定途径可能有助于填补这一空白。我们以前已经表明，在哺乳动物细胞中，剥夺必需的氨基酸（甲硫氨酸/半胱氨酸或酪氨酸）导致转录激活的整合沉默转基因，包括质粒和逆转录病毒载体和潜伏的HIV-1前病毒，通过一个过程，涉及表观遗传染色质重塑和组蛋白乙酰化。在这里，我们表明，甲硫氨酸/半胱氨酸的剥夺也导致内源性逆转录病毒的转录上调，这表明必需的AA饥饿不仅影响外源性非天然DNA序列的表达，而且还影响内源性基因组的古老整合和沉默的寄生元件。此外，我们表明，转基因再激活反应是高度保守的，在不同的哺乳动物细胞类型，它是可重复的剥夺最重要的氨基酸。一般控制非去阻遏2（GCN 2）激酶和下游整合应激反应代表了介导这一过程的最佳候选者;然而，通过药理学方法，RNA干扰和基因组编辑，我们证明它们不受影响。相反，这种反应需要MEK/ERK和/或JNK活性，并由核糖体抑制剂复制，这表明它是由一种新的营养传感和信号传导途径触发的，由核糖体的翻译阻断启动，不依赖于mTOR和GCN 2。总的来说，这些研究结果指出，一个一般的转录响应基本AA剥夺，影响非天然基因组序列的表达，与相关的影响AA限制在健康和疾病的表观遗传/转录效应。
In a variety of species, reduced food intake, and in particular protein or amino acid (AA) restriction, extends lifespan and healthspan. However, the underlying epigenetic and/or transcriptional mechanisms are largely unknown, and dissection of specific pathways in cultured cells may contribute to filling this gap. We have previously shown that, in mammalian cells, deprivation of essential AAs (methionine/cysteine or tyrosine) leads to the transcriptional reactivation of integrated silenced transgenes, including plasmid and retroviral vectors and latent HIV-1 provirus, by a process involving epigenetic chromatic remodeling and histone acetylation. Here we show that the deprivation of methionine/cysteine also leads to the transcriptional upregulation of endogenous retroviruses, suggesting that essential AA starvation affects the expression not only of exogenous non-native DNA sequences, but also of endogenous anciently-integrated and silenced parasitic elements of the genome. Moreover, we show that the transgene reactivation response is highly conserved in different mammalian cell types, and it is reproducible with deprivation of most essential AAs. The General Control Non-derepressible 2 (GCN2) kinase and the downstream integrated stress response represent the best candidates mediating this process; however, by pharmacological approaches, RNA interference and genomic editing, we demonstrate that they are not implicated. Instead, the response requires MEK/ERK and/or JNK activity and is reproduced by ribosomal inhibitors, suggesting that it is triggered by a novel nutrient-sensing and signaling pathway, initiated by translational block at the ribosome, and independent of mTOR and GCN2. Overall, these findings point to a general transcriptional response to essential AA deprivation, which affects the expression of non-native genomic sequences, with relevant implications for the epigenetic/transcriptional effects of AA restriction in health and disease.
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影响因子：
50.3
作者：
Di Biase S;Lee C;Brandhorst S;Manes B;Buono R;Cheng CW;Cacciottolo M;Martin-Montalvo A;de Cabo R;Wei M;Morgan TE;Longo VD
通讯作者：
Longo VD
严格控制核糖体依赖性激活。
影响因子：
64.8
作者：
Brown A;Fernández IS;Gordiyenko Y;Ramakrishnan V
通讯作者：
Ramakrishnan V
影响因子：
5.5
作者：
Buzdin AA;Prassolov V;Garazha AV
通讯作者：
Garazha AV
影响因子：
10.5
作者：
Cherkasova, VA;Hinnebusch, AG
通讯作者：
Hinnebusch, AG
影响因子：
64.5
作者：
Fontana L;Partridge L
通讯作者：
Partridge L