Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma.针对人类高级别胶质瘤的基因组学研究，已发现了已知的肿瘤驱动基因与潜在候选驱动基因。细胞培养与小鼠模型相关研究对上述工作进行了补充，同时鉴定出了更多与胶质瘤发生（gliomagenesis）相关的基因及生物学过程。此前我们的研究发现，从小鼠Rosa26基因座（Rosa26 locus）全身范围内激活睡美人转座子（Sleeping Beauty transposon），可引发低外显率（penetrance）的胶质瘤发生。本研究报道了转座子在胶质纤维酸性蛋白（Glial Fibrillary Acidic Protein, GFAP）阳性细胞区域内被激活的小鼠模型的特征分析结果。在纯合野生型遗传背景下，该类小鼠未出现胶质瘤；但当转座子激活发生于p19ARF（p19Arf）杂合遗传背景时，可观察到极少数胶质瘤病例。通过克隆Rosa26基因座区域转座子激活诱导的额外胶质瘤样本中的插入位点，本研究鉴定出多个胶质瘤候选基因。将上述候选基因与人类胶质瘤的基因组、表观基因组及mRNA表达数据进行比对后，可推定其中多个基因为人类胶质母细胞瘤（glioblastoma）中的抑癌基因与癌基因。