Open AccessRegulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency
Author(s) -
Boqiang Sun,
Xiao Yang,
Fujun Hou,
Xiaofeng Yu,
Qiongyan Wang,
Hyung Suk Oh,
Patuan Raja,
Jean M. Pesola,
Emilia A. H. Vanni,
Seamus McCarron,
Jenna MorrisLove,
Alex H. M. Ng,
George M. Church,
David M. Knipe,
Donald M. Coen,
Dongli Pan
Publication year - 2021
Publication title -
nature microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.305
H-Index - 79
ISSN - 2058-5276
DOI - 10.1038/s41564-020-00860-1
Subject(s) - lytic cycle , biology , gene silencing , gene knockdown , virus latency , herpes simplex virus , transcription (linguistics) , viral replication , gene , rna interference , microrna , microbiology and biotechnology , virology , virus , rna , genetics , linguistics , philosophy
MicroRNA miR-138, which is highly expressed in neurons, represses herpes simplex virus 1 (HSV-1) lytic cycle genes by targeting viral ICP0 messenger RNA, 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 RNA sequencing/photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation followed by short interfering RNA knockdown of candidate targets, we identified the host Oct-1 and Foxc1 messenger mRNAs as miR-138's targets, whose gene products are transcription factors important for HSV-1 replication in neuronal cells. OCT-1 has a known role in the 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.