PDF(Pubmed)
Abstract：
SNCAIP duplication may promote Group 4 medulloblastoma via induction of PRDM6, a poorly characterized member of the PRDF1 and RIZ1 homology domain-containing (PRDM) family of transcription factors. Here, we investigated the function of PRDM6 in human hindbrain neuroepithelial stem cells and tested PRDM6 as a driver of Group 4 medulloblastoma. We report that human PRDM6 localizes predominantly to the nucleus, where it causes widespread repression of chromatin accessibility and complex alterations of gene expression patterns. Genome-wide mapping of PRDM6 binding reveals that PRDM6 binds to chromatin regions marked by histone H3 lysine 27 trimethylation that are located within, or proximal to, genes. Moreover, we show that PRDM6 expression in neuroepithelial stem cells promotes medulloblastoma. Surprisingly, medulloblastomas derived from PRDM6-expressing neuroepithelial stem cells match human Group 3, but not Group 4, medulloblastoma. We conclude that PRDM6 expression has oncogenic potential but is insufficient to drive Group 4 medulloblastoma from neuroepithelial stem cells. We propose that both PRDM6 and additional factors, such as specific cell-of-origin features, are required for Group 4 medulloblastoma. Given the lack of PRDM6 expression in normal tissues and its oncogenic potential shown here, we suggest that PRDM6 inhibition may have therapeutic value in PRDM6-expressing medulloblastomas.
摘要：
SNCAIP复制可能通过诱导PRDM6促进第4组髓母细胞瘤，PRDM6是PRDF1和RIZ1同源结构域（PRDM）转录因子家族的特征不佳的成员。这里,我们研究了PRDM6在人后脑神经上皮干细胞中的功能,并测试了PRDM6作为第4组髓母细胞瘤的驱动因子.我们报告说，人类PRDM6主要定位于细胞核，它引起染色质可及性的广泛抑制和基因表达模式的复杂改变。PRDM6结合的全基因组定位揭示了PRDM6结合到由组蛋白H3赖氨酸27三甲基化标记的染色质区域，或者接近，基因。此外，我们证明PRDM6在神经上皮干细胞中的表达促进髓母细胞瘤的发生。令人惊讶的是,源自表达PRDM6的神经上皮干细胞的髓母细胞瘤与人第3组匹配,但与第4组髓母细胞瘤不匹配。我们得出结论，PRDM6表达具有致癌潜力，但不足以从神经上皮干细胞驱动第4组髓母细胞瘤。我们建议PRDM6和其他因素，例如特定的细胞起源特征，4组髓母细胞瘤需要。鉴于PRDM6在正常组织中缺乏表达及其致癌潜力，我们认为抑制PRDM6可能在表达PRDM6的髓母细胞瘤中具有治疗价值.
