Nature Cell Biology ( IF 17.3 ) Pub Date : 2024-07-18 , DOI: 10.1038/s41556-024-01460-5 Olivier Saulnier , Jamie Zagozewski , Lisa Liang , Liam D. Hendrikse , Paul Layug , Victor Gordon , Kimberly A. Aldinger , Parthiv Haldipur , Stephanie Borlase , Ludivine Coudière-Morrison , Ting Cai , Emma Martell , Naomi M. Gonzales , Gareth Palidwor , Christopher J. Porter , Stéphane Richard , Tanveer Sharif , Kathleen J. Millen , Brad W. Doble , Michael D. Taylor , Tamra E. Werbowetski-Ogilvie
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OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein–protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression.
中文翻译:
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第 3 组髓母细胞瘤干细胞程序由 OTX2 介导的选择性剪接维持
OTX2 是髓母细胞瘤 (MB) 中的转录因子和已知驱动因素,它在肿瘤的子集中扩增,并在第 3 组和第 4 组 MB 的大多数病例中过表达。在这里,我们展示了 OTX2 在 3 MB 组选择性剪接中的非规范作用。 OTX2 通过蛋白质-蛋白质相互作用与大量剪接调节复合物结合,并调节干细胞剪接程序。 OTX2可以直接或间接结合RNA,这可能部分独立于其DNA调节功能。 OTX2控制促肿瘤发生剪接程序,该程序反映在人类小脑菱形唇起源中。在OTX2调控的差异剪接基因中,PPHLN1在最原始的菱形唇干细胞中表达,靶向PPHLN1剪接可减少肿瘤生长并提高体内存活率。这些发现确定 OTX2 介导的选择性剪接是驱动第 3 组 MB 进展的细胞命运决定的主要决定因素。