2. Academic Validation
  3. 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

  • Nat Microbiol. 2021 May;6(5):682-696. doi: 10.1038/s41564-020-00860-1.
Boqiang Sun  # 1 2 3,  Xuewei Yang  # 1 2 4,  Fujun Hou  # 1 2,  Xiaofeng Yu 1 2 5,  Qiongyan Wang 1 2,  Hyung Suk Oh 6,  Priya Raja 6,  Jean M Pesola 7,  Emilia A H Vanni 7,  Seamus McCarron 7,  Jenna Morris-Love 7 8,  Alex H M Ng 9 10,  George M Church 9 10,  David M Knipe 6,  Donald M Coen 7,  Dongli Pan 11 12
Affiliations

Affiliations

  • 1 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 3 Thermo Fisher Scientific, Shanghai, China.
  • 4 Innovent Biologics, Inc., Suzhou, China.
  • 5 Zhejiang Chinese Medical University, Hangzhou, China.
  • 6 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 7 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 8 Graduate Program in Pathobiology, Brown University, Providence, RI, USA.
  • 9 Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA.
  • 10 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 11 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China. pandongli@zju.edu.cn.
  • 12 Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. pandongli@zju.edu.cn.
  • # Contributed equally.
PMID: 33558653 DOI: 10.1038/s41564-020-00860-1
Abstract

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.

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