Regulation of host and virus genes by neuronal miR-138 favours herpes simplex virus 1 latency
Authors: Xiaofeng Yu
Fujun Hou
Hyung Suk Oh
Emilia A H Vanni
Jean M Pesola
Jenna Morris-Love
Dongli Pan
Qiongyan Wang
Alex H M Ng
Seamus McCarron
Boqiang Sun
David M Knipe
Priya Raja
Xuewei Yang
George M Church
Donald M Coen
Journal: Nature Microbiology (2021)
Discipline: MICROBIOLOGY
Keywords: MicroRNA miR-138; herpes simplex virus 1 (HSV-1); ICP0; Oct-1; Foxc1
Affiliations: Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China., Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China., Thermo Fisher Scientific, Shanghai, China., Innovent Biologics, Inc., Suzhou, China., Zhejiang Chinese Medical University, Hangzhou, China., Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Graduate Program in Pathobiology, Brown University, Providence, RI, USA., Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA., Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, China. ., Department of Infectious Diseases of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. .

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. 

Retracted: No

PubPeer comments:
 Figure 6(d). Much more similar than you would expect, yet experimental conitions different. https: imgur.com r1zWVtm , 
 #1 I believe this false color image supports your concerns. Could the authors please post the original uncropped scans? *** ![file] ,