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Circular RNA enrichment in platelets is a signature of transcriptome degradation

Lookup NU author(s): Dr Jannetta Steyn, Professor David Elliott, Dr Mauro Santibanez Koref, Dr Michael Jackson

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Society of Hematology, 2016.

For re-use rights please refer to the publisher's terms and conditions.


Abstract

In platelets, splicing and translation occur in the absence of a nucleus. However, the integrity and stability of mRNAs derived from megakaryocyte progenitor cells remain poorly quantified on a transcriptome-wide level. As circular RNAs (circRNAs) are resistant to degradation by exonucleases, their abundance relative to linear RNAs can be used as a surrogate marker for mRNA stability in the absence of transcription. Here we show that circRNAs are enriched in human platelets 17- to 188-fold relative to nucleated tissues and 14- to 26-fold relative to samples digested with RNAseRto selectively remove linear RNA. We compare RNAseq read depths inside and outside circRNAs to provide in silico evidence of transcript circularity, show that exons within circRNAs are enriched on average 12.7 times in platelets relative to nucleated tissues and identify 3162 genes significantly enriched for circRNAs, including some where all RNAseq reads appear to be derived from circular molecules. We also confirm that this is a feature of other anucleate cells through transcriptome sequencing of mature erythrocytes, demonstrate that circRNAs are not enriched in cultured megakaryocytes, and demonstrate that linear RNAs decay more rapidly than circRNAs in platelet preparations. Collectively, these results suggest that circulating platelets have lost >90% of their progenitor mRNAs and that translation in platelets occurs against the backdrop of a highly degraded transcriptome. Finally, we find that transcripts previously classified as products of reverse transcriptase template switching are both enriched in platelets and resistant to decay, countering the recent suggestion that up to 50% of rearranged RNAs are artifacts.


Publication metadata

Author(s): Alhasan A, Izuogu OG, Al-Balool HH, Steyn JS, Evans A, Colzani M, Ghevaert C, Mountford JC, Marenah L, Elliott DJ, Santibanez-Koref M, Jackson MS

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2016

Volume: 127

Issue: 9

Pages: E1-E11

Print publication date: 03/03/2016

Online publication date: 10/12/2015

Acceptance date: 01/12/2015

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2015-06-649434

DOI: 10.1182/blood-2015-06-649434


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