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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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Research Article Cell biology Oncology Article has an altmetric score of 25

RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma

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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 8

A group of RBPs modulate the AS landscape in glioma.

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A group of RBPs modulate the AS landscape in glioma.
(A) Motif analysis ...
(A) Motif analysis around the splice sites of the exons from the 200 events and predicted binding RBPs. (B) Upper, dot plot showing the correlation between AS score and the expression of each RBPs. Dot sizes indicate the P value from spearman correlation analysis, and colors indicate correlation coefficient value. Bottom, heatmap showing the expression of each RBPs in TCGA gliomas, iPSC glioma xenografts, and human ESC to MN differentiation model. (C) IB analysis of indicated RBPs in normal brains (NB), NU glioma tissues with low or high AS scores (ASlo and AShi), and indicated cell lines. (D) IHC staining shows the expression of PTBP1 and RBFOX1 in iPSC glioma xenografts. Scale bars: 20 μm. (E) Heatmaps show the PSI distribution of the events that are from the 200 events and affected by PTBP1-KD, RBFOX1-OE, or SRSF3-KO. RT-PCR shows the validation of AS changes in GSC1485 with indicated treatment. The numbers below the PCR plots show the PCR-quantified PSI values.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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