期刊
GENES
卷 10, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/genes10020141
关键词
METTL3; m(6)A; GSCs; glioblastoma; histone activation; splicing; RNA editing; m(6)A reader
资金
- DST, Government of India [EMR/2016/000838]
- DBT, Government of India [BT/COE/34/SP15885/2016]
- DST-FIST
- DBT
- UGC (Centre for Advanced Studies in Molecular Microbiology)
Despite recent advances in N-6-methyladenosine (m(6)A) biology, the regulation of crucial RNA processing steps by the RNA methyltransferase-like 3 (METTL3) in glioma stem-like cells (GSCs) remains obscure. An integrated analysis of m(6)A-RIP (RNA immunoprecipitation) and total RNA-Seq of METTL3-silenced GSCs identified that m(6)A modification in GSCs is principally carried out by METTL3. The m(6)A-modified transcripts showed higher abundance compared to non-modified transcripts. Further, we showed that the METTL3 is essential for the expression of GSC-specific actively transcribed genes. Silencing METTL3 resulted in the elevation of several aberrant alternative splicing events. We also found that putative m(6)A reader proteins play a key role in the RNA stabilization function of METTL3. METTL3 altered A-to-I and C-to-U RNA editing events by differentially regulating RNA editing enzymes ADAR and APOBEC3A. Similar to protein-coding genes, lincRNAs (long intergenic non-coding RNAs) with m(6)A marks showed METTL3-dependent high expression. m(6)A modification of 3'UTRs appeared to result in a conformation-dependent hindrance to miRNA binding to their targets. The integrated analysis of the m(6)A regulome in METTL3-silenced GSCs showed global disruption in tumorigenic pathways that are indispensable for GSC maintenance and glioma progression. We conclude that METTL3 plays a vital role in many steps of RNA processing and orchestrates successful execution of oncogenic pathways in GSCs.
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