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

in Proceedings of the National Academy of Sciences of the United States of America by 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

TLDR

  • The study investigates how a protein called NSUN5 helps regulate the way that cells make a type of RNA called m5C. This RNA is important for the growth of a type of brain tumor called malignant glioma. The study finds that NSUN5 helps remove a protein called β-catenin, which is important for the growth of the tumor. The study also finds that NSUN5 helps remove another type of RNA called 5hmC, which is important for the immune system to fight the tumor. The study suggests that blocking the way that NSUN5 works could be a way to treat malignant glioma.

Abstract

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 Feand 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 correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Overview

  • The study investigates the role of the immune checkpoint CD47 in malignant glioma and the impact of RNA 5-methylcytosine (m5C) modification on tumor pathogenesis and the immune microenvironment. The study uses the canonical 28SrRNA methyltransferase NSUN5 as a model to understand the mechanism underlying m5C-modified RNA metabolism and its contribution to glioma immune evasion. The study aims to identify the key players involved in this process and explore potential therapeutic strategies for glioma immune therapy.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, including the effect of NSUN5 on β-catenin degradation, TET2 recruitment, and RBFOX2-mediated degradation of 5hmC caRNA. The study identifies NSUN5 as a key player in regulating RNA metabolism and its contribution to glioma immune evasion. The study also finds that pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo.

Implications and Future Directions

  • The study's findings highlight the importance of understanding the mechanism underlying m5C-modified RNA metabolism in glioma immune evasion and suggest potential therapeutic strategies for glioma immune therapy. The study identifies NSUN5 as a potential target for glioma immune therapy and highlights the need for further research to explore its role in regulating RNA metabolism and its contribution to glioma immune evasion. The study also suggests the need for further research to explore the potential of combining pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling to enhance TAM-based phagocytosis and glioma elimination in vivo.
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