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N6-Methyladenosine Landscape of Glioma Stem-Like Cells: METTL3 Is Essential for the Expression of Actively Transcribed Genes and Sustenance of the Oncogenic Signaling

1
Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India
2
Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(2), 141; https://doi.org/10.3390/genes10020141
Received: 28 September 2018 / Revised: 22 November 2018 / Accepted: 28 November 2018 / Published: 13 February 2019
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

Despite recent advances in N6-methyladenosine (m6A) 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 m6A-RIP (RNA immunoprecipitation) and total RNA-Seq of METTL3-silenced GSCs identified that m6A modification in GSCs is principally carried out by METTL3. The m6A-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 m6A 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 m6A marks showed METTL3-dependent high expression. m6A modification of 3′UTRs appeared to result in a conformation-dependent hindrance to miRNA binding to their targets. The integrated analysis of the m6A 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. View Full-Text
Keywords: METTL3; m6A; GSCs; glioblastoma; histone activation; splicing; RNA editing; m6A reader METTL3; m6A; GSCs; glioblastoma; histone activation; splicing; RNA editing; m6A reader
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Visvanathan, A.; Patil, V.; Abdulla, S.; Hoheisel, J.D.; Somasundaram, K. N6-Methyladenosine Landscape of Glioma Stem-Like Cells: METTL3 Is Essential for the Expression of Actively Transcribed Genes and Sustenance of the Oncogenic Signaling. Genes 2019, 10, 141.

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