Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency.

Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency.
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通过神经元miR-138调节宿主和病毒基因有利于单纯疱疹病毒1型潜伏期。

DOI:
10.1038/s41564-020-00860-1
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发表时间:
2021-05
影响因子:
28.3
通讯作者:
Pan D
Pan D
中科院分区:
生物学1区
文献类型:
--
作者:
Sun B;Yang X;Hou F;Yu X;Wang Q;Oh HS;Raja P;Pesola JM;Vanni EAH;McCarron S;Morris-Love J;Ng AHM;Church GM;Knipe DM;Coen DM;Pan D

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MicroRNA miR-138, which is highly expressed in neurons, represses herpes simplex virus 1 (HSV-1) lytic-cycle genes by targeting viral ICP0 mRNA, thereby promoting viral latency in mice. We found that overexpressed miR-138 also represses lytic processes independently of ICP0 in murine and human neuronal cells, therefore we investigated whether miR-138 has targets besides ICP0. Using genome-wide RNAseq/PAR-CLIP followed by siRNA knockdown of candidate targets, we identified host transcription factors Oct-1 and Foxc1 as targets of miR-138 that are important for HSV-1 replication in neuronal cells. Oct-1 has a known role in initiation of HSV transcription. Overexpression of Foxc1, which was not known to affect HSV-1, promoted HSV-1 replication in murine neurons and ganglia. CRISPR/Cas9 knockout of Foxc1 reduced viral replication, lytic gene expression, and miR-138 repression in murine neuronal cells. Foxc1 also collaborated with ICP0 to decrease heterochromatin on viral genes and compensated for the defect of an ICP0-null virus. In summary, miR-138 targets ICP0, Oct-1 and Foxc1 to repress HSV-1 lytic-cycle genes and promote epigenetic gene silencing, which together enable favourable conditions for latent infection.
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