The YTHDC1 reader protein recognizes and regulates the lncRNA MEG3 following its METTL3-mediated m6A methylation: a novel mechanism early during radiation-induced liver injury

作者：Gui-yuan Song, Qinghua Yu, Xue-kun Xing, Xinming Fan, Siguang Xu, Wenbo Zhang, Yaoyao Wu, Nan Zhang, Tian-zhu Chao, Fei Wang, Chen Ding, Cun-yang Guo, Liyuan Ma, Chang-ye Sun, Shu-yan Duan, Ping Xu · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07417-2 · 被引用次数：9 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Circular RNAs in diseases

Abstract 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.