University of Cambridge > > Babraham Seminar > Post-transcriptional gene dysregulation in human asthma as determined by Frac-seq.

Post-transcriptional gene dysregulation in human asthma as determined by Frac-seq.

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Asthma is a chronic inflammatory disease of the airways affecting 350 million people worldwide and 5.5 million people in the UK. Around 5-10% of asthmatics have severe asthma (SA), characterised by poor response to therapy including high dose of inhaled and oral corticosteroids. These patients are at significant risk and represent a major unmet clinical need. The underlying pathophysiological mechanisms of severe asthma remain inadequately understood, and little is known about post-transcriptional processes taking place in airway cells from patients with asthma. We have combined Frac-seq with small RNA -sequencing to determine changes at the post-transcriptional level in bronchial epithelial cells from healthy controls and severe asthmatics. Frac-seq consists on subcellular fractionation and RNA -seq, determining total (cytoplasmic) and polyribosome-bound (engaged in translation) mRNA levels. We detected 319 differentially expressed mRNAs at the cytoplasmic level and 335 transcripts differentially bound to polyribosomes between health and asthma, which overlapped in only 15% candidates. Differential gene expression analysis (analysing all mRNAs that map to a given gene) was able to detect 30% of the changes determined when alternative splicing analysis was performed. The differentially expressed mRNAs in both fractions, cytoplasmic and polyribosome-bound, mapped to different biological pathways, suggestive of post-transcriptional dysregulation in severe asthma affecting distinct pathophysiological mechanisms. Amongst the differentially expressed microRNAs, a network of only 6 microRNAs potentially regulates 50% of the changes detected in mRNA translation and account for 90% of all cellular microRNA targeting, with preference for mRNAs bound to polyribosomes. Modified in bronchial epithelial cells from healthy donors, this microRNA hub mimics severe asthma characteristics such as corticosteroid resistance. As microRNAs regulate 50% translational changes in SA, the remaining 50% of changes may be due to dysregulated RNA binding proteins (RBPs) in these cells. We are investigating the role that RNA binding proteins have in the regulation of corticosteroid insensitivity as well as rhinovirus responses. Taken together, our results demonstrate the essential importance of assessing post-transcriptional gene expression and regulation in human asthma, which we hope will open new paths for therapeutics development.

This talk is part of the Babraham Seminar series.

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