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BMC Genomics. 2018 Apr 20;19(1):276. doi: 10.1186/s12864-018-4660-7.

Analysis of human ES cell differentiation establishes that the dominant isoforms of the lncRNAs RMST and FIRRE are circular.

Author information

1
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
2
Present Address: The European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, CB10 1SD, UK.
3
Present Address: Institute of Cellular Medicine, William Leech Building, Medical School, Newcastle University, Newcastle-upon-Tyne, NE2 4HH, UK.
4
Present Address: Lions Eye Institute, 2 Verdun Street, Nedlands, WA, 6009, Australia.
5
Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. michael.jackson@newcastle.ac.uk.

Abstract

BACKGROUND:

Circular RNAs (circRNAs) are predominantly derived from protein coding genes, and some can act as microRNA sponges or transcriptional regulators. Changes in circRNA levels have been identified during human development which may be functionally important, but lineage-specific analyses are currently lacking. To address this, we performed RNAseq analysis of human embryonic stem (ES) cells differentiated for 90 days towards 3D laminated retina.

RESULTS:

A transcriptome-wide increase in circRNA expression, size, and exon count was observed, with circRNA levels reaching a plateau by day 45. Parallel statistical analyses, controlling for sample and locus specific effects, identified 239 circRNAs with expression changes distinct from the transcriptome-wide pattern, but these all also increased in abundance over time. Surprisingly, circRNAs derived from long non-coding RNAs (lncRNAs) were found to account for a significantly larger proportion of transcripts from their loci of origin than circRNAs from coding genes. The most abundant, circRMST:E12-E6, showed a > 100X increase during differentiation accompanied by an isoform switch, and accounts for > 99% of RMST transcripts in many adult tissues. The second most abundant, circFIRRE:E10-E5, accounts for > 98% of FIRRE transcripts in differentiating human ES cells, and is one of 39 FIRRE circRNAs, many of which include multiple unannotated exons.

CONCLUSIONS:

Our results suggest that during human ES cell differentiation, changes in circRNA levels are primarily globally controlled. They also suggest that RMST and FIRRE, genes with established roles in neurogenesis and topological organisation of chromosomal domains respectively, are processed as circular lncRNAs with only minor linear species.

PMID:
29678151
PMCID:
PMC5910558
DOI:
10.1186/s12864-018-4660-7
[Indexed for MEDLINE]
Free PMC Article

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