RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma
Xiao Song, … , Bo Hu, Shi-Yuan Cheng
Xiao Song, … , Bo Hu, Shi-Yuan Cheng
Published April 25, 2024
Citation Information: J Clin Invest. 2024;134(11):e173789. https://doi.org/10.1172/JCI173789.
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RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma

Abstract

Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.

Authors

Xiao Song, Deanna Tiek, Shunichiro Miki, Tianzhi Huang, Minghui Lu, Anshika Goenka, Rebeca Iglesia, Xiaozhou Yu, Runxin Wu, Maya Walker, Chang Zeng, Hardik Shah, Shao Huan Samuel Weng, Allen Huff, Wei Zhang, Tomoyuki Koga, Christopher Hubert, Craig M. Horbinski, Frank B. Furnari, Bo Hu, Shi-Yuan Cheng

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Figure 2

An overview of the 200 events and validation of their AS pattern.

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An overview of the 200 events and validation of their AS pattern. (A) Di...
(A) Distribution of the 200 AS events in each category: SE, skipped exons; MXE, mutually exclusive exons; A5SS/A3SS, alternative 5′/3′ splice sites; RI, retained introns. (B) Functional impact of 200 AS events annotated by the ASpedia database. PTM, posttranslational modification; NMD, nonsense-mediated decay. (C) Top 5 significantly enriched GO biological processes of the 170 genes. (D) Volcano plot for the differential expression of 170 AS-affected genes between samples with high and low AS scores from TCGA data set. (E) AS profiling in human ESC-derived neuronal differentiation model. Left, Heatmaps show the AS landscape of 200 events in ESCs, differentiated NPCs, and motor neurons (MNs). Right, AS scores in indicated groups. (F and G) AS scores in normal brains (NB), IDH-mut, and IDH-WT gliomas from TCGA (F) and NU (G) data sets. (H) AS scores in indicated cell types from scRNA-Seq data of adult and fetal brains. (I) RT-PCR analysis with isoform-specific primers for indicated genes in normal brains (NB), NU glioma tissues (ASlo and AShi), GSC/GBM cell lines, and normal human neural progenitors (NHNPs). (J) Pearson correlation analysis between MISO-estimated PSI and RT-PCR quantified PSI. Data were analyzed using 1-way ANOVA multiple comparisons with correction by controlling the FDR in E–H. *P < 0.05; **P < 0.01; ***P < 0.001.