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J Immunol. 2018 Jul 1;201(1):251-263. doi: 10.4049/jimmunol.1701798. Epub 2018 May 16.

Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq.

Author information

1
School of Immunology and Microbial Sciences, Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London, London SE19RT, United Kingdom; rocio.martinez_nunez@kcl.ac.uk.
2
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, United Kingdom.
3
Southampton National Institute for Health Research Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research, University Hospital Southampton National Health Service Foundation Trust, Southampton SO16 6YD, United Kingdom.
4
Centre for Inflammation and Tissue Repair, Department of Respiratory Medicine, Rayne Institute, University College London, London WC1E 6JF, United Kingdom; and.
5
School of Electronics and Computer Science, University of Southampton, Southampton SO17 1BJ, United Kingdom.

Abstract

MicroRNAs are small noncoding RNAs that inhibit gene expression posttranscriptionally, 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 subcellular fractionation and RNA sequencing (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 (i.e., 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 (i.e., 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 posttranscriptional gene dysregulation in human asthma, in which microRNAs play a central role, illustrating the feasibility and importance of assessing posttranscriptional gene expression when investigating human disease.

PMID:
29769273
PMCID:
PMC6013048
DOI:
10.4049/jimmunol.1701798
[Indexed for MEDLINE]
Free PMC Article

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