NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion

作者：Ruixin Wu, Chunming Sun, Xi Chen, Runyue Yang, Yuxuan Luan, Xiang Zhao, Panpan Yu, Rongkui Luo, Yingyong Hou, Ruotong Tian, Shasha Bian, Yuli Li, Yinghua Dong, Qian Liu, Weiwei Dai, Zhuoyang Fan, Rucheng Yan, Binyang Pan, Siheng Feng, Jing Wu, Fangzhen Chen, Changle Yang, Hanlin Wang, Haochen Dai, Minfeng Shu · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2321611121 · 被引用次数：54 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Epigenetics and DNA Methylation

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates β-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of β-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe 2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlat...