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

Genome-wide posttranscriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq.
Genome-wide posttranscriptional dysregulation by microRNAs in human asthma as revealed by Frac-seq.
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.
Martinez-Nunez, Rocio, Teresa
2db66b88-3e6d-4b53-b741-fce5d7b950aa
Rupani, Hitasha
cbc7068a-4279-4c8e-b83f-353210711062
Platé, Manuela
b0c30b16-03e7-49a3-9a38-5d7b07a97a8c
Niranjan, Mahesan
5cbaeea8-7288-4b55-a89c-c43d212ddd4f
Chambers, Rachel C.
a9a457b3-2dc5-4ff0-9ed3-dbb3a6901ed7
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d
Martinez-Nunez, Rocio, Teresa
2db66b88-3e6d-4b53-b741-fce5d7b950aa
Rupani, Hitasha
cbc7068a-4279-4c8e-b83f-353210711062
Platé, Manuela
b0c30b16-03e7-49a3-9a38-5d7b07a97a8c
Niranjan, Mahesan
5cbaeea8-7288-4b55-a89c-c43d212ddd4f
Chambers, Rachel C.
a9a457b3-2dc5-4ff0-9ed3-dbb3a6901ed7
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Sanchez-Elsner, Tilman
b8799f8d-e2b4-4b37-b77c-f2f0e8e2070d

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. (doi:10.4049/jimmunol.1701798).

Record type: Article

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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Accepted/In Press date: 17 April 2018
e-pub ahead of print date: 16 May 2018

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Local EPrints ID: 421143
URI: https://eprints.soton.ac.uk/id/eprint/421143
PURE UUID: 29873977-a8c8-4fca-ab3b-bb7b9f18e11d

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Date deposited: 23 May 2018 16:30
Last modified: 13 Mar 2019 18:28

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Contributors

Author: Rocio, Teresa Martinez-Nunez
Author: Hitasha Rupani
Author: Manuela Platé
Author: Rachel C. Chambers

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