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

摘要

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 forpolyribosome-bound mRNAs. Transfection of this hub in bronchial epithelial cellsfrom healthy donors mimicked asthma characteristics. Our work demonstratesextensive post-transcriptional gene dysregulation in human asthma, wheremicroRNAs play a central role, illustrating the feasibility and importance ofassessing post-transcriptional gene expression when investigating humandisease.