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

Research output: Contribution to journalArticle

Rocio T. Martinez-Nunez, Hitasha Rupani, Manuela Plate, Mahesan Niranjan, Rachel Chambers, Peter Howarth, Tilman Sanchez-Elsner

Original languageEnglish
Pages (from-to)251-263
JournalThe Journal of Immunology
Early online date16 May 2018
DOIs
Publication statusE-pub ahead of print - 16 May 2018

King's Authors

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 pathophysiological mechanisms related to bronchoepithelium disclosed solely by polyribosome-bound mRNAs (e.g., IL1A and LTB genes or ITGA6 and ITGA2 alternatively spliced isoforms). 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 bronchial epithelial cells from healthy donors mimicked asthma characteristics. Our work demonstrates extensive post-transcriptional gene dysregulation in human 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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