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Identification of targets of miR-138 in Neuro-2a and 293T cells by RNAseq

ABSTRACT: We previously showed that miR-138 can repress herpes simplex virus 1 (HSV-1) ICP0 expression by binding to ICP0 mRNA. However, in this study we found that miR-138 can also repress viral gene expression independent of ICP0. We did not find other confirmed viral targets of miR-138. Therefore we conducted these RNAseq experiments (in combination with PAR-CLIP experiments whose results are uploaded separately) to identify host targets of miR-138 in two cell lines to explain the ICP0-independent effects on HSV-1 gene expression.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE127502 | GEO | 2020/04/27

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) play roles in diverse developmental and disease processes. Distinct miRNAs have hundreds to thousands of conserved mRNA binding sites, but typically direct only modest repression via single sites. Cotargeting of individual mRNAs by different miRNAs could potentially achieve stronger and more complex patterns of repression. Comparing target sets of different miRNAs, we identified hundreds of pairs of miRNAs that share more mRNA targets than expected (often by two-fold or more) relative to stringent controls, with particularly high levels of cotargeting among brain-enriched miRNAs. We profiled miRNA expression changes over a cell culture model of neuronal differentiation, and selected the non-homologous cotargeting miRNA pair miR-138 and miR-137 to study functionally. We generated a CRISPR-mediated mir-138 double knockout (DKO) cell line in the murine CAD cell culture model of neuronal differentiation. mir-138 DKO cells lacking both mir-138 loci were unable to differentiate and project neurites following serum withdrawal. Further characterization of the DKO cells by RNA-seq showed that loss of miR-138 resulted in a de-differentiated state compared to WT cells. Specificity of the mir-138 DKO was confirmed by the rescue of neurite growth upon addition of a miR-138 mimic. Interestingly, addition of a miR-137 mimic, but not mimics of other neuronal miRNAs, could also rescue the neurite growth phenotype and allow mir-138 DKO cells to differentiate, and transcriptome profiling revealed similar gene expression changes. Clustering of all cotargeting pairs revealed a group of 9 predominantly brain-enriched miRNAs that share many targets. In reporter assays, subsets of these miRNAs together repressed gene expression by 5- to 10-fold, often exhibiting cooperative repression. Together, our results uncover an unexpected pattern in which combinations of miRNAs collaborate to robustly repress cotargets, and suggest important developmental roles for cotargeting.

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Identification of targets of miR-138 in Neuro-2a and 293T cells by RNAseq

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