2. Academic Validation
  3. Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes

Neuronal miR-9 promotes HSV-1 epigenetic silencing and latency by repressing Oct-1 and Onecut family genes

  • Nat Commun. 2024 Mar 5;15(1):1991. doi: 10.1038/s41467-024-46057-6.
Yue Deng 1 2 3,  Yuqi Lin 1 2 3,  Siyu Chen 1 2 3,  Yuhang Xiang 1 2 3,  Hongjia Chen 1 2 3,  Shuyuan Qi 1 2 3,  Hyung Suk Oh 4,  Biswajit Das 4 5,  Gloria Komazin-Meredith 5 6,  Jean M Pesola 5,  David M Knipe 4,  Donald M Coen 5,  Dongli Pan 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, Zhejiang, China.
  • 4 Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • 6 Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.
  • 7 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. pandongli@zju.edu.cn.
  • 8 Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. pandongli@zju.edu.cn.
  • 9 Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou, Zhejiang, China. pandongli@zju.edu.cn.
PMID: 38443365 DOI: 10.1038/s41467-024-46057-6
Abstract

Herpes simplex virus 1 (HSV-1) latent Infection entails repression of viral lytic genes in neurons. By functional screening using luciferase-expressing HSV-1, we identify ten neuron-specific MicroRNAs potentially repressing HSV-1 neuronal replication. Transfection of miR-9, the most active candidate from the screen, decreases HSV-1 replication and gene expression in Neuro-2a cells. Ectopic expression of miR-9 from lentivirus or recombinant HSV-1 suppresses HSV-1 replication in male primary mouse neurons in culture and mouse trigeminal ganglia in vivo, and reactivation from latency in the primary neurons. Target prediction and validation identify transcription factors Oct-1, a known co-activator of HSV transcription, and all three Onecut family members as miR-9 targets. Knockdown of ONECUT2 decreases HSV-1 yields in Neuro-2a cells. Overexpression of each ONECUT protein increases HSV-1 replication in Neuro-2a cells, human induced pluripotent stem cell-derived neurons, and primary mouse neurons, and accelerates reactivation from latency in the mouse neurons. Mutagenesis, ChIP-seq, RNA-seq, ChIP-qPCR and ATAC-seq results suggest that ONECUT2 can nonspecifically bind to viral genes via its CUT domain, globally stimulate viral gene transcription, reduce viral heterochromatin and enhance the accessibility of viral chromatin. Thus, neuronal miR-9 promotes viral epigenetic silencing and latency by targeting multiple host transcription factors important for lytic gene activation.

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