Published on Feb. 13, 2019 in Genes (Basel) volume 10(2).

PubMed ID: 30781903

DOI: genes10020141

Abstract:

Despite recent advances in N⁶-methyladenosine (m⁶A) biology, the regulation ofcrucial RNA processing steps by the RNA methyltransferase-like 3 (METTL3) in gliomastem-like cells (GSCs) remains obscure. An integrated analysis of m⁶A-RIP (RNAimmunoprecipitation) and total RNA-Seq of METTL3-silenced GSCs identified that m⁶Amodification in GSCs is principally carried out by METTL3. The m⁶A-modifiedtranscripts showed higher abundance compared to non-modified transcripts. Further,we showed that the METTL3 is essential for the expression of GSC-specific activelytranscribed genes. Silencing METTL3 resulted in the elevation of several aberrantalternative splicing events. We also found that putative m⁶A reader proteins play akey role in the RNA stabilization function of METTL3. METTL3 altered A-to-I andC-to-U RNA editing events by differentially regulating RNA editing enzymes ADAR andAPOBEC3A. Similar to protein-coding genes, lincRNAs (long intergenic non-codingRNAs) with m⁶A marks showed METTL3-dependent high expression. m⁶A modification of3'UTRs appeared to result in a conformation-dependent hindrance to miRNA binding totheir targets. The integrated analysis of the m⁶A regulome in METTL3-silenced GSCsshowed global disruption in tumorigenic pathways that are indispensable for GSCmaintenance and glioma progression. We conclude that METTL3 plays a vital role inmany steps of RNA processing and orchestrates successful execution of oncogenicpathways in GSCs.