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Discovery of Novel Non-Coding RNAs in the Perinatal Lung by Deep Sequencing

Presented at the Neonatal Society 2014 Autumn Meeting.

Belteki G1,2, Sweeney D2, Andrews S3, Hughes M4, Smith GCS2

1 Department of Neonatology, Cambridge University Hospital NHS Foundation Trust, UK
2 Department of Obstetrics and Gynaecology, University of Cambridge, UK
3 Babraham Institute, Babraham, Cambridge, UK
4 Centre for Genomic Research, University of Liverpool, UK

Background:Perinatal lung maturation is characterized by widespread gene expression changes that are tightly regulated. Recently, a role of regulatory non-coding RNAs in developmental processes has been reported. Short micro RNAs are essential for normal lung development as mice lacking the miRNA processing enzyme DICER die after the birth due to neonatal respiratory failure. The role of longer non-coding RNAs (lncRNAs) in the perinatal lung is unknown. We set out to identify and characterize novel non-coding RNAs in the perinatal lung. 

Methods: We isolated both long and short RNAs from mouse lungs at the early canalicular stage of development (embryonic day 16.5, n=5) and at the saccular stage (embryonic day 18.5, n=5). Using Illumina sequencing we sequenced over 200 million small RNA reads and over 500 million paired long RNA reads from both developmental stages. We mapped to sequences to the known mouse protein-coding and non-coding genes. We identified genes differentially expressed at a significance level of p<0.01. Selected genes were validated by real-time quantitiative RT-PCR. Our work was supported by Addenbrookes Charitable Trust (ACT).

Results: We found that 424 protein-coding genes were up-regulated and 230 genes were down-regulated over 5-fold during lung maturation. Genes participating in inflammatory and defence responses and in ion transport were significantly (p<0.01) over-represented among up-regulated genes. Genes involved in DNA replication and cell cycle control were over-represented among down-regulated genes. In addition, we found 16 microRNAs and 44 novel long non-coding RNAs differentially regulated. All these non-coding genes are conserved and are also present in humans. Of them, miR-146a and miR-146b attenuate the cytokine response to inflammatory stimuli in adult lung cells and miR-486 is known to have an anti-proliferative effect in lung tumours. Both miR-22 and its host gene (miR22hg), a long noncoding RNA, are turned on in saccular stage lungs. We present an integrative analysis of these non-coding RNAs and their putative regulatory targets.

Conclusion: The transcriptional program of lung maturation includes novel microRNAs and long non-coding RNAs of unknown function. These genes are potential therapeutic targets and warrant further investigations.

Corresponding author: gusztav.belteki@addenbrookes.nhs.uk

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