PDF(Pubmed)
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.
摘要：
OTX2是髓母细胞瘤（MB）中的转录因子和已知驱动因子，其中它在肿瘤的子集中扩增，并在第3组和第4组的大多数病例中过表达MB。在这里，我们证明了OTX2在3MB组选择性剪接中的非规范作用。OTX2通过蛋白质-蛋白质相互作用与剪接调节子复合物的大组装相关联,并调节干细胞剪接程序。OTX2可以直接或间接结合RNA,并且这可以部分独立于其DNA调节功能。OTX2控制在人类小脑菱形唇起源中反映的促肿瘤性剪接程序。在OTX2调控的差异剪接基因中，PPHLN1表达于最原始的菱形唇干细胞，和靶向PPHLN1剪接减少肿瘤生长并增强体内存活。这些发现将OTX2介导的选择性剪接确定为驱动组3MB进展的细胞命运决定的主要决定因素。
