Background:Medulloblastoma is an aggressive pediatric brain tumor characterized by marked molecular heterogeneity, which significantly impacts prognosis. The low frequency of genomic mutations in medulloblastoma suggests that alternative mechanisms, such as epigenetic regulation, may play a critical role in its pathogenesis.Methods:Using the EpiFactors database, we investigated the expression of epigenetic regulators in two independent RNA sequencing cohorts [Pediatric Brain Tumor Atlas (PBTA) and Williamson], stratified by molecular subgroups and clinical outcomes. We further analyzed expression heterogeneity at the single-cell level in malignant medulloblastoma cells using single-cell RNA sequencing.Results:Members of the SWI/SNF superfamily were dysregulated across all four molecular subtypes of medulloblastoma. Subtype-specific alterations were also observed: the acetyltransferase complex was shared between Group 3 (with SMARCD3 as a potential marker) and Group 4 (with RBM24 as a potential marker); SWR1, β-catenin/TCF, and protein–DNA complexes were specifically enriched in SHH-MB (with EYA1 and SATB2 as SHH markers); and RSC-type, PRC1, DNA polymerase complexes, and X-chromosome-related factors were enriched in WNT-MB (with FOXA1 and PIWIL4 as WNT markers). An epigenetic score (epi-score), linked to RNA metabolism and S-adenosyl-L-methionine pathways, was developed and identified as an independent adverse prognostic factor. High epi-scores were associated with proliferative, stem-like SHH malignant cells (characterized by G2/M phase, low pseudotime, and high entropy), exhibiting alterations in RNA splicing, DNA recombination, and nuclear division.Conclusions:Expression heterogeneity of epigenetic regulators is closely associated with molecular subgroups and clinical outcomes in medulloblastoma. These findings highlight the role of epigenetic dysregulation in RNA metabolism and tumor progression, particularly in SHH-driven proliferative cells.
背景：髓母细胞瘤是一种侵袭性儿童脑肿瘤，其显著分子异质性对预后具有重要影响。该肿瘤基因组突变频率较低，提示表观遗传调控等替代机制可能在其发病机制中起关键作用。 方法：利用EpiFactors数据库，我们在两个独立的RNA测序队列[儿童脑肿瘤图谱（PBTA）和Williamson队列]中，按分子亚型和临床结局分层研究了表观遗传调控因子的表达情况。进一步通过单细胞RNA测序分析了恶性髓母细胞瘤细胞在单细胞水平的表达异质性。 结果：SWI/SNF超家族成员在所有四种髓母细胞瘤分子亚型中均出现失调。同时观察到亚型特异性改变：乙酰转移酶复合物在Group3（以SMARCD3为潜在标志物）和Group4（以RBM24为潜在标志物）中共同存在；SWR1、β-catenin/TCF及蛋白质-DNA复合物特异性富集于SHH亚型（以EYA1和SATB2为SHH标志物）；而RSC型、PRC1、DNA聚合酶复合物及X染色体相关因子在WNT亚型中富集（以FOXA1和PIWIL4为WNT标志物）。我们构建了与RNA代谢及S-腺苷-L-蛋氨酸通路相关的表观遗传评分（epi-score），该评分被确定为独立不良预后因素。高表观遗传评分与增殖性、干细胞样SHH恶性细胞（具有G2/M期、低伪时序值和高熵值特征）相关，这些细胞表现出RNA剪接、DNA重组及核分裂过程的异常。 结论：表观遗传调控因子的表达异质性与髓母细胞瘤的分子亚型及临床结局密切相关。这些发现揭示了表观遗传失调在RNA代谢和肿瘤进展中的作用，特别是在SHH驱动的增殖细胞中。
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