SRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion

被引：11

作者：

Conn, Vanessa M. ^{[1
,2
]}

Gabryelska, Marta ^{[1
,2
]}

Marri, Shashikanth ^{[1
,2
]}

Stringer, Brett W. ^{[1
,2
,3
]}

Ormsby, Rebecca J. ^{[1
,2
]}

Penn, Timothy ^{[1
,2
]}

Poonnoose, Santosh ^{[2
,4
]}

Kichenadasse, Ganessan ^{[2
,5
]}

Conn, Simon J. ^{[1
,2
]}

机构：

[1] Flinders Univ S Australia, Coll Med & Publ Hlth, Flinders Canc Res, Bedford Pk, SA 5042, Australia

[2] Flinders Univ S Australia, Coll Med & Publ Hlth, Flinders Hlth & Med Res Inst FHMRI, Bedford Pk, SA 5042, Australia

[3] Univ Queensland, Sch Clin Med, Greenslopes Clin Unit, Brisbane, Qld 4120, Australia

[4] Flinders Univ S Australia, Dept Neurosurg, Bedford Pk, SA 5042, Australia

[5] Flinders Med Ctr, Flinders Ctr Innovat Canc, Dept Med Oncol, Bedford Pk, SA 5042, Australia

来源：

CELLS | 2020年 / 9卷 / 11期

基金：

澳大利亚研究理事会; 英国医学研究理事会;

关键词：

circular RNAs; alternative splicing; splicing factors; microexons; SRRM4; glioblastoma; BIOGENESIS; MECHANISM; DISCOVERY; DATABASE;

D O I：

10.3390/cells9112488

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：17

共 66 条

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