Human cytomegalovirus infection perturbs neural progenitor cell fate via the expression of viral microRNAs

Abstract

Human cytomegalovirus (HCMV) preferentially targets neural progenitor cells (NPCs) in congenitally infected fetal brains, inducing neurodevelopmental disorders. While HCMV expresses several microRNAs (miRNAs) during infection, their roles in NPC infection are unclear. Here, we characterized expression of cellular and viral miRNAs in HCMV‐infected NPCs during early infection by microarray and identified seven differentially expressed cellular miRNAs and six significantly upregulated HCMV miRNAs. Deep learning approaches were used to identify potential targets of significantly upregulated HCMV miRNAs against differentially expressed cellular messenger RNA (mRNAs), and the associations with miRNA‐mRNA expression changes were observed. Gene ontology enrichment analysis indicated cellular gene targets were significantly enriched in pathways involved in neurodevelopment and cell‐cycle processes. Viral modulation of selected miRNAs and cellular gene targets involved in neurodevelopmental processes were further validated by real‐time quantitative reverse transcription polymerase chain reaction. Finally, a predicted 3′ untranslated region target site of hcmv‐miR‐US25‐1 in Jag1, a factor important for neurogenesis, was confirmed by mutagenesis. Reduction of Jag1 RNA and protein levels in NPCs was observed in response to transient expression of hcmv‐miR‐US25‐1. A hcmv‐miR‐US25‐1 mutant virus (ΔmiR‐US25) displayed limited ability to downregulate Jag1 mRNA levels and protein levels during the early infection stage compared with the wild type virus. Our collective experimental and computational investigation of miRNAs and cellular mRNAs expression in HCMV‐infected NPCs yields new insights into the roles of viral miRNAs in regulating NPC fate and their contributions to HCMV neuropathogenesis.

MicroRNA expression profiling of urine exosomes in children with congenital cytomegalovirus infection

“…Changes in miRNA expression may reflect impaired neurodevelopment. Recently, Jiang et al 21 characterized cellular and viral miRNA expression during CMV infection in neural progenitor cells. In their study, of the seven differentially expressed cellular miRNAs, miR-1246 was upregulated in CMV-infected cells; miR-1246 was also upregulated in the ScCMV group (FDR-adjusted p = 0.01, fold-change = 10.96) and included in the top-50 significantly differentially expressed miRNAs in our study.…”

Regulation of Onecut2 by miR-9-5p in Japanese encephalitis virus infected neural stem/progenitor cells

“…One such host factors are miRNAs. These small non-coding RNAs have an important role in fine tuning the gene expression in NSCs during neurotropic viral infections ( 40 – 42 ). Previous reports by our group have established how NSC fate determination and self-renewal capacity are abrogated during JEV infection and how abundance of certain host miRNAs was getting affected post JEV infection in NSCs ( 24 , 35 ).…”

MiR-199a-5P promotes osteogenic differentiation of human stem cells from apical papilla via targeting IFIT2 in apical periodontitis

“…MiRNAs are an evolutionarily conserved set of small non-coding RNAs of approximately 18-22 nucleotides, and display their functions mainly via binding to the 3′ untranslated regions leading to degradation or post-transcriptional repression of the mRNA targets ( 17 ). Studies have previously implicated the essential regulatory roles of miRNAs in diverse biological or pathological processes, including tumor metastasis, cellular differentiation, proliferation, apoptosis, and tissue development ( 18 – 20 ). The pivotal roles of miRNAs in osteogenesis, such as osteoblast differentiation, angiogenesis, and intra-chondral bone formation have also been identified ( 21 – 23 ).…”