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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.

Authors
  • Visvanathan, Abhirami1
  • Patil, Vikas2
  • Abdulla, Shibla3
  • Hoheisel, Jörg D4
  • Somasundaram, Kumaravel5
  • 1 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. [email protected] , (India)
  • 2 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. [email protected] , (India)
  • 3 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. [email protected] , (India)
  • 4 Functional Genome Analysis, Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. [email protected] , (Germany)
  • 5 Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. [email protected] , (India)
Type
Published Article
Journal
Genes
Publisher
MDPI AG
Publication Date
Feb 13, 2019
Volume
10
Issue
2
Identifiers
DOI: 10.3390/genes10020141
PMID: 30781903
Source
Medline
Keywords
Language
English
License
Unknown

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.

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