Epigenetic regulation of SARS-Cov-2 spike protein modulates cellular viability and nascent RNA transcription in neuronal cells.
Epigenetic regulation of SARS-Cov-2 spike protein modulates cellular viability and nascent RNA transcription in neuronal cells.
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DOI：
10.1016/j.gendis.2023.04.001
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发表时间：
2023-05-08
期刊：
影响因子：
6.8
通讯作者：
Yin, Shigang
中科院分区：
文献类型：
--
作者：
Kong, Xi;Lu, Peng;Zhang, Jinyue;Bao, Zheng;Kuang, Chenghao;Xie, Bingqing;Peng, Jianhua;Ma, Ning;Jiang, Yong;Yin, Shigang
已证明SARS-CoV-2对神经元和神经胶质样细胞高度敏感，但关于该病毒在神经入侵后如何影响神经元尚无共识。因此，尚不清楚SARS-CoV-2是否以及如何维持神经元细胞的稳态。在此，我们发现SARS-CoV-2刺突蛋白的受体结合域（RBD）作为细胞外重塑成分，破坏表观遗传调控，扰乱新生RNA （nsRNA）转录，促进线粒体生物发生，提高SH-SY5Y细胞的细胞活力。RBD蛋白通过促进KDM6B的表达，降低H3K27me3的表达。下调KDM6B能够降低先前由所有RBD突变体（K417N/L452R/T478K: KLT; L452R/E484Q: LE; N501Y）介导的分子和细胞异常，包括NRF2表达水平、ROS清除能力、线粒体活性和细胞增殖能力。此外，我们还研究了RBD蛋白是否从表观遗传学上影响线粒体生物发生。用LE突变体处理后，ChIP-qPCR显示H3K27me3在NRF2启动子区域受到抑制，导致NRF2激活。因此，本研究揭示了SARS-CoV-2 RBD蛋白通过细胞外信号转导通道调控线粒体生物发生并重塑神经元细胞增殖的一种新的表观遗传机制。COVID-19逃避免疫系统的能力及其快速传播都与RBD蛋白的突变密切相关。2为了确定RBD蛋白是否可以增强细胞活力，我们用RBD蛋白培养SH-SY5Y细胞（图1a）。最后，我们发现RBD蛋白以剂量依赖的方式增加细胞活力（图1b）。LE突变体表现出最大的细胞活力改善，从107%提高到116%（图2）。1 C)。然而，在呼吸上皮HBE细胞中没有观察到结果，这表明这种效应可能，至少部分是神经元细胞特异性的（图1 D-F）。特别是，所有RBD蛋白都能提高细胞的增殖能力（图1g）。因此，我们的研究表明RBD蛋白可能影响神经细胞的增殖。
SARS-CoV-2 has been demonstrated to be highly susceptible to neuron-and glial-like cells, 1 but there is no consensus regarding how the virus affects neurons following neuroinvasion. It is therefore unknown if and how SARS-CoV-2 maintains the homeostasis of neuronal cells. Herein, we revealed that the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein acted as an extracellular remodeling component to undermine epigenetic regulation, perturb nascent RNA (nsRNA) transcription, promote mitochondrial biogenesis, and increase cellular viability in SH-SY5Y cells. Through boosting the expression of KDM6B, RBD proteins decreased H3K27me3. Down-regulation of KDM6B was able to decrease molecular and cellular abnormalities previously mediated by all RBD mutants (K417N/L452R/T478K: KLT; L452R/E484Q: LE; N501Y), including NRF2 expression levels, ROS scavenging capacity, mitochondrial activity, and cell proliferation capacity. Further, we also investigated whether RBD proteins affected mitochondrial biogenesis epigenetically. After treatment with the LE mutant, ChIP-qPCR revealed that H3K27me3 was repressed in the NRF2 promoter regions, resulting in NRF2 activating. This study, therefore, uncovered a novel epigenetic mechanism by which SARS-CoV-2 RBD proteins regulate mitochondrial biogenesis via an extracellular signal transduction channel and remodel neuronal cell proliferation.COVID-19's ability to evade the immune system and its fast dissemination are both tightly linked to mutations in RBD proteins. 2 To determine whether RBD proteins may enhance cellular viability, SH-SY5Y cells were grown with RBD proteins (Fig. 1 A). Finally, we identified that RBD proteins increased cellular viability in a dose-dependent manner (Fig. 1 B). The LE mutant exhibited the greatest improvement in cellular viability, from 107% to 116%(Fig. 1 C). However, the results were not observed in respiratory epithelial HBE cells, suggesting that this effect may, at least in part, be specific to neuronal cells (Fig. 1 D–F). Particularly, all RBD proteins could improve the proliferative capability of cells (Fig. 1 G). Hence, our research suggests that RBD proteins could affect neural cell proliferation.
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神秘的不稳定转录本与血液阶段恶性疟原虫中发育调节的基因表达有关
影响因子：
4.1
作者：
Yin, Shigang;Fan, Yanting;Zhang, Qingfeng
通讯作者：
Zhang, Qingfeng
DOI：
10.1073/pnas.2200960119
发表时间：
2022-08-30
影响因子：
11.1
作者：
通讯作者：
--
影响因子：
5.6
作者：
Laffeber C;de Koning K;Kanaar R;Lebbink JHG
通讯作者：
Lebbink JHG
影响因子：
11.4
作者：
Ni, Hong-Min;Williams, Jessica A.;Ding, Wen-Xing
通讯作者：
Ding, Wen-Xing