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March 30th, 2025
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Northwestern University
genomics
biorxiv

A Single-Cell Atlas of RNA Alternative Splicing in the Glioma-Immune Ecosystem

Song, X.Open in Google Scholar•Tiek, D.Open in Google Scholar•Lu, M.Open in Google Scholar•Yu, X.Open in Google Scholar•Wu, R.Open in Google Scholar•Walker, M.Open in Google Scholar•He, Q.Open in Google Scholar•Sisbarro, D.Open in Google Scholar•Hu, B.Open in Google Scholar•Cheng, S.-Y.Open in Google Scholar

Single-cell analysis has refined our understanding of cellular heterogeneity in glioma, yet RNA alternative splicing (AS) - a critical layer of transcriptome regulation - remains underexplored at single-cell resolution. Here, we present a pan-glioma single-cell AS analysis in both tumor and immune cells through integrating seven SMART-seq2 datasets of human gliomas. Our analysis reveals lineage-specific AS across glioma cellular states, with the most divergent AS landscapes between mesenchymal- and neuronal-like glioma cells, exemplified by AS in TCF12 and PTBP2. Comparison between core and peripheral glioma cells highlights AS-redox co-regulation of cytoskeleton organization. Further analysis of glioma-infiltrating immune cells reveals potential isoform-level regulation of protein glycosylation in regulatory T cells and a link between MS4A7 AS in macrophages and clinical response to anti-PD-1 therapy. This study emphasizes the role of AS in glioma cellular heterogeneity, highlighting the importance of an isoform-centric approach to better understand the complex biological processes driving tumorigenesis.

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