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bioRxiv · 10.1101/234500

Genome-wide post-transcriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq

Martinez-Nunez, R. T.·Rupani, H.·Plate, M.·Niranjan, M.·Chambers, R. C.·Howarth, P. H.·Sanchez-Elsner, T.
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Abstract

MicroRNAs are small non-coding RNAs that inhibit gene expression post-transcriptionally, implicated in virtually all biological processes. Although the effect of individual microRNAs is generally studied, the genome-wide role of multiple microRNAs is less investigated. We assessed paired genome-wide expression of microRNAs with total (cytoplasmic) and translational (polyribosome-bound) mRNA levels employing Frac-seq in human primary bronchoepithelium from healthy controls and severe asthmatics. Severe asthma is a chronic inflammatory disease of the airways characterized by poor response to therapy. We found genes (=all isoforms of a gene) and mRNA isoforms differentially expressed in asthma, with novel inflammatory and structural mechanisms disclosed solely by polyribosome-bound mRNAs. Gene expression (=all isoforms of a gene) and mRNA expression analysis revealed different molecular candidates and biological pathways, with differentially expressed polyribosome-bound and total mRNAs also showing little overlap. We reveal a hub of six dysregulated microRNAs accounting for [~]90% of all microRNA targeting, displaying preference for polyribosome-bound mRNAs. Transfection of this hub in healthy cells mimicked asthma characteristics. Our work demonstrates extensive post-transcriptional gene dysregulation in asthma, where microRNAs play a central role, illustrating the feasibility and importance of assessing post-transcriptional gene expression when investigating human disease.

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Martinez-Nunez, R. T., Rupani, H., Plate, M., Niranjan, M., Chambers, R. C., Howarth, P. H., Sanchez-Elsner, T.. 2017-12-15. Genome-wide post-transcriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq. https://doi.org/10.1101/234500

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