DOI: 10.1101/2023.05.20.541583

Epitranscriptomics m6A analyses reveal distinct m6A marks under tumor necrosis α (TNF-α)-induced apoptotic conditions in HeLa cells

A. A.Alasar O. Tuncel B. Saglam Y. Gazaloglu M. Atbinek U. Cagiral E. Iscan G. Ozhan B. Akgul

A. A.Alasar O. Tuncel B. Saglam ...+5 B. Akgul

摘要

TNF- is a ligand that induces both intrinsic and extrinsic apoptotic pathways in HeLa cells by modulating complex gene regulatory mechanisms. However, the full spectrum of TNF-- modulated epitranscriptomic m6A marks is unknown. We employed a genomewide approach to examine the extent of m6A RNA modifications under TNF--modulated apoptotic conditions in HeLa cells. miCLIP-seq analyses revealed a plethora of m6A marks on 632 target mRNAs with an enrichment on 99 mRNAs associated with apoptosis. Interestingly, the m6A RNA modification patterns were quite different under cisplatin- and TNF--mediated apoptotic conditions. We then examined the abundance and translational efficiencies of several mRNAs under METTL3 knockdown and/or TNF- treatment conditions. Our analyses showed changes in the translational efficiency of TP53INP1 mRNA based on the polysome profile analyses. Additionally, TP53INP1 protein amount was modulated by METTL3 knockdown upon TNF- treatment but not CP treatment, suggesting the existence of a pathway-specific METTL3-TP53INP1 axis. Congruently, METLL3 knockdown sensitized HeLa cells to TNF--mediated apoptosis, which was also validated in a zebrafish larval xenograft model. These results suggest that apoptotic pathway- specific m6A methylation marks exist in cells and TNF--METTL3-TP53INP1 axis modulates TNF--mediated apoptosis in HeLa cells.

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