The YTHDC1 reader protein recognizes and regulates the lncRNA MEG3 following its METTL3-mediated m(6)A methylation: a novel mechanism early during radiation-induced liver injury.

While apoptotic cell death is known to be central to the pathogenesis of radiation-induced liver injury (RILI), the mechanistic basis for this apoptotic activity remains poorly understood. N(6)-methyladenosine (m(6)A) modifications are the most common form of reversible methylation observed on lncRNAs in eukaryotic cells, with their presence leading to pronounced changes in the activity of a range of biological processes. The degree to which m(6)A modification plays a role in the induction of apoptotic cell death in response to ionizing radiation (IR) in the context of RILI remains to be established. Here, IR-induced apoptosis was found to significantly decrease the levels of m(6)A present, with a pronounced decrease in the expression of methyltransferase-like 3 (METTL3) at 2 d post radiation in vitro. From a mechanistic perspective, a methylated RNA immunoprecipitation assay found that lncRNA MEG3 was a major METTL3 target. The expression of MEG3 was upregulated via METTL3-mediated m(6)A in a process that was dependent on YTHDC1, ultimately reversing the miR-20b-mediated inhibition of BNIP2 expression. Together, these findings demonstrate that the responsivity of METTL3 activity to IR plays a role in IR-induced apoptotic cell death, leading to the reverse of miR-20b-mediated BNIP2 inhibition through the YTHDC1-dependent m(6)A modification of MEG3, suggesting that this process may play a central role in RILI incidence.