Genome-wide posttranscriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq.

Martinez-Nunez, Rocio, Teresa, Rupani, Hitasha, Platé, Manuela, Niranjan, Mahesan, Chambers, Rachel C., Howarth, Peter H. and Sanchez-Elsner, Tilman (2018) Genome-wide posttranscriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq. The Journal of Immunology, 201 (1), 251-263. (doi:10.4049/jimmunol.1701798).

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.

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Contributors

Author: Mahesan Niranjan

Author: Tilman Sanchez-Elsner

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