加拿大曼尼托巴大学Tamra E. Werbowetski-Ogilvie和加拿大病童医院Michael D. Taylor小组合作的最新研究发现，由OTX2介导的可变剪接可维持第3组髓母细胞瘤（MB）的干细胞程序。相关论文于2024年7月18日发表在《自然-细胞生物学》杂志上。

研究人员揭示了OTX2在第3组MB可变剪接中的非典型作用。OTX2通过蛋白质与蛋白质之间的相互作用与剪接调节器复合物结合，并调节干细胞剪接程序。OTX2可直接或间接结合RNA，这可能部分独立于其DNA调控功能。OTX2调控一种促肿瘤生长的剪接程序，这种程序在人小脑菱形唇起源中得到反映。

在OTX2调控的不同剪接基因中，PPHLN1在最原始的菱形唇干细胞中表达，针对PPHLN1的剪接可减少肿瘤生长并提高存活率。

这些研究结果表明，OTX2介导的可变剪接是细胞命运决定的主要决定因素，而细胞命运决定是第3组MB进展的驱动力。

据了解，OTX2是一种转录因子，也是已知的髓母细胞瘤驱动因子，它在部分肿瘤中扩增，并在大多数第3组和第4组MB病人中过表达。

附：英文原文

Title: A group 3 medulloblastoma stem cell program is maintained by OTX2-mediated alternative splicing

Author: Saulnier, Olivier, Zagozewski, Jamie, Liang, Lisa, Hendrikse, Liam D., Layug, Paul, Gordon, Victor, Aldinger, Kimberly A., Haldipur, Parthiv, Borlase, Stephanie, Coudire-Morrison, Ludivine, Cai, Ting, Martell, Emma, Gonzales, Naomi M., Palidwor, Gareth, Porter, Christopher J., Richard, Stphane, Sharif, Tanveer, Millen, Kathleen J., Doble, Brad W., Taylor, Michael D., Werbowetski-Ogilvie, Tamra E.

Issue&Volume: 2024-07-18

Abstract: 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.

DOI: 10.1038/s41556-024-01460-5

Source: https://www.nature.com/articles/s41556-024-01460-5