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Open AccessArticle

SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion

1
Flinders Cancer Research, College of Medicine and Public Health, Flinders University, Bedford Park 5042, South Australia, Australia
2
Flinders Health and Medical Research Institute (FHMRI), College of Medicine and Public Health, Flinders University, Bedford Park 5042, South Australia, Australia
3
School of Clinical Medicine-Greenslopes Clinical Unit, The University of Queensland, Brisbane 4120, Queensland, Australia
4
Department of Neurosurgery, Flinders Medical Centre, Bedford Park 5042, South Australia, Australia
5
Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park 5042, South Australia, Australia
*
Author to whom correspondence should be addressed.
Cells 2020, 9(11), 2488; https://doi.org/10.3390/cells9112488
Received: 6 October 2020 / Revised: 27 October 2020 / Accepted: 13 November 2020 / Published: 16 November 2020
(This article belongs to the Special Issue Circular RNAs: Non-canonical Observations on Non-canonical RNAs)
High-throughput RNA sequencing (RNA-seq) and dedicated bioinformatics pipelines have synergized to identify an expansive repertoire of unique circular RNAs (circRNAs), exceeding 100,000 variants. While the vast majority of these circRNAs comprise canonical exonic and intronic sequences, microexons (MEs)—which occur in 30% of functional mRNA transcripts—have been entirely overlooked. CircRNAs which contain these known MEs (ME-circRNAs) could be identified with commonly utilized circRNA prediction pipelines, CIRCexplorer2 and CIRI2, but were not previously recognized as ME-circRNAs. In addition, when employing a bespoke bioinformatics pipeline for identifying RNA chimeras, called Hyb, we could also identify over 2000 ME-circRNAs which contain novel MEs at their backsplice junctions, that are uncalled by either CIRCexplorer2 or CIRI2. Analysis of circRNA-seq datasets from gliomas of varying clinical grades compared with matched control tissue has shown circRNAs have potential as prognostic markers for stratifying tumor from healthy tissue. Furthermore, the abundance of microexon-containing circRNAs (ME-circRNAs) between tumor and normal tissues is correlated with the expression of a splicing associated factor, Serine/arginine repetitive matrix 4 (SRRM4). Overexpressing SRRM4, known for regulating ME inclusion in mRNAs critical for neural differentiation, in human HEK293 cells resulted in the biogenesis of over 2000 novel ME-circRNAs, including ME-circEIF4G3, and changes in the abundance of many canonical circRNAs, including circSETDB2 and circLRBA. This shows SRRM4, in which its expression is correlated with poor prognosis in gliomas, acts as a bona fide circRNA biogenesis factor. Given the known roles of MEs and circRNAs in oncogenesis, the identification of these previously unrecognized ME-circRNAs further increases the complexity and functional purview of this non-coding RNA family. View Full-Text
Keywords: circular RNAs; alternative splicing; splicing factors; microexons; SRRM4; glioblastoma circular RNAs; alternative splicing; splicing factors; microexons; SRRM4; glioblastoma
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MDPI and ACS Style

Conn, V.M.; Gabryelska, M.; Marri, S.; Stringer, B.W.; Ormsby, R.J.; Penn, T.; Poonnoose, S.; Kichenadasse, G.; Conn, S.J. SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion. Cells 2020, 9, 2488. https://doi.org/10.3390/cells9112488

AMA Style

Conn VM, Gabryelska M, Marri S, Stringer BW, Ormsby RJ, Penn T, Poonnoose S, Kichenadasse G, Conn SJ. SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion. Cells. 2020; 9(11):2488. https://doi.org/10.3390/cells9112488

Chicago/Turabian Style

Conn, Vanessa M.; Gabryelska, Marta; Marri, Shashikanth; Stringer, Brett W.; Ormsby, Rebecca J.; Penn, Timothy; Poonnoose, Santosh; Kichenadasse, Ganessan; Conn, Simon J. 2020. "SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion" Cells 9, no. 11: 2488. https://doi.org/10.3390/cells9112488

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