Deregulating m6A regulators leads to altered RNA biology in glioma cell lines
Year: 2024
Type: preprint
Abstract: glioma model following knockdown (KD) of the reader IGF2BP2, writer METTL3, and eraser ALKBH5, with naive glioma cells and astrocytes as controls. Glioma cells exhibited a two-fold reduction in global m6A, suggesting progressive loss from healthy to malignant states. Integrated analysis revealed that m6A mediated control of gene expression is influenced by modification topology (CDS:3'UTR), transcript biotype, and length. Regulator KD, particularly ALKBH5 induced redistribution of m6A toward 3'UTR with consequent gene upregulation. We also identified m6A-mediated isoform switching, with a higher usage of retained intron and nonsense-mediated decay isoforms. Structural and splicing alterations at the isoform level were identified unique to each KD condition indicating m6A driven aberrant alternative splicing. At the functional level, KD specific remodeling of oncogenic signaling was also observed. ALKBH5 KD suppressed MYC targets and pro-apoptotic signaling while METTL3 KD enhanced mTOR and PI3K-AKT signaling. Collectively, these results demonstrate that m6A mediated regulation in glioma is highly context-dependent, defining distinct clinically relevant phenotypes. This has implications for future biomarker discovery and development of targeted therapeutics.
Authors: Syeda Maheen Batool, Hanna Lee, Ana K. Escobedo, Denalda Gashi, Kesli Faber, Prerna Khanna, Kase D. Haas, Tiffaney Hsia, Bob S. Carter, Leonora Balaj
Institutions: Harvard University, Massachusetts General Hospital
Language: English
Topic: RNA modifications and cancer
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Cancer Institute
OpenAlex ID: W4403914074