Genome-Wide Posttranscriptional Dysregulation by MicroRNAs in Human Asthma as Revealed by Frac-seq.
Rocio Teresa Martinez-NunezHitasha RupaniManuela PlatéMahesan NiranjanRachel C ChambersPeter H HowarthTilman Sanchez-ElsnerPublished in: Journal of immunology (Baltimore, Md. : 1950) (2018)
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.
Keyphrases
- genome wide
- dna methylation
- gene expression
- endothelial cells
- copy number
- chronic obstructive pulmonary disease
- lung function
- single cell
- induced pluripotent stem cells
- genome wide identification
- pluripotent stem cells
- allergic rhinitis
- cystic fibrosis
- mass spectrometry
- transcription factor
- rna seq
- bone marrow
- single molecule
- high speed
- high resolution
- kidney transplantation
- mesenchymal stem cells