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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1587009

This article is part of the Research Topic Post-Transcriptional Modifications in Cancer Immunity and Immunotherapy View all 5 articles

Multi-Omics Landscape of Alternative Splicing in Diffuse Midline Glioma Reveals Immune-and Neural-Driven Subtypes with Implications for Spliceosome-Targeted Therapy

Provisionally accepted
Hui Yang Hui Yang *Chaxian Liu Chaxian Liu Yue Liu Yue Liu Hao Lin Hao Lin Chufan Zhang Chufan Zhang Bilong Zhang Bilong Zhang Haikun Song Haikun Song Xiaomin Fan Xiaomin Fan Yi Lyu Yi Lyu Ying Mao Ying Mao *
  • Fudan University, Shanghai, China

The final, formatted version of the article will be published soon.

    Introduction: H3K27-altered diffuse midline glioma (DMG) is a highly aggressive glioma subtype, accounting for approximately 60% of pediatric high-grade gliomas, with a median survival of less than 12 months. Due to its predominant localization in the brainstem, conventional surgical resection is often unfeasible, underscoring the urgent need for alternative therapeutic strategies. While previous studies on DMG have primarily focused on regulatory mechanisms at the protein level, the role of alternative splicing in DMG remains largely unexplored. Given its potential impact on gene regulation and tumor progression, a comprehensive analysis of alternative splicing could provide novel insights into targeted or immune therapeutic strategies, complementing existing transcriptomic studies of DMG.To investigate the alternative splicing landscape of DMG, we performed transcriptome sequencing (RNA-seq) on patient-derived H3WT and H3K27-altered DMG cell lines, integrating these data with RNA-seq and single-cell transcriptomic (scRNA-seq) datasets from published sources. This comprehensive approach enabled us to delineate the alternative splicing landscape of H3K27-altered DMG and validate its distinct features at the cellular level.Our multi-omics analysis revealed significant transcriptional alterations in H3K27-altered DMG compared to H3WT DMG, particularly in pathways related to neuro-regulation, metabolism, and immunity.Further in-depth analysis identified extensive alternative splicing changes in H3K27-altered DMG, predominantly associated with RNA modifications and key alterations in extracellular matrix and nucleotide metabolism. Integrating these findings, we characterized five RNA-associated proteins that enabled a binary classification of DMG into neural and immune subtypes, with each subtype exhibiting distinct prognostic and transcriptomic features. Notably, we identified RALYL as a potential key regulator in DMG progression.Our findings indicate that H3K27-altered DMG exhibits significant alternative splicing alterations, which play crucial roles in tumorigenesis and progression. Additionally, our study identified an RNA-binding protein-based classification of DMG and characterized RALYL as a potential regulatory factor, highlighting its potential as a novel therapeutic target.

    Keywords: DMG, H3K27-altered, multi-omics, Alternative Splicing, Metabolism, immune, Posttranscriptional modifications, tumorigenesis

    Received: 03 Mar 2025; Accepted: 28 Mar 2025.

    Copyright: © 2025 Yang, Liu, Liu, Lin, Zhang, Zhang, Song, Fan, Lyu and Mao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Hui Yang, Fudan University, Shanghai, China
    Ying Mao, Fudan University, Shanghai, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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