胶质瘤恶性进展相关基因PASG敲除后基因表达谱的改变

目的探索胶质瘤恶性进展相关PASG基因与胶质瘤发生发展的关系。方法选择性敲除PASG基因7.126kb基因组DNA序列(含该基因第10～12个外显子),并从形态学及全基因组基因表达水平观察基因敲除后的改变。结果PASG基因敲除鼠全基因组表现为低甲基化水平。海马区皮层的大锥体细胞存在细胞形态、排列层次和数量的异常。鼠脑全基因组差异基因表达谱分析显示:PASG基因敲除后,表达差异超过1.6倍的基因共有123条,其中61条表达下调,62条表达上调。结论PASG基因作为上游调控基因,通过改变基因组甲基化水平调控下游一系列细胞增殖分化相关基因表达。PASG基因表达异常导致下游相关基因的表观遗传修饰改变可能是胶质瘤发生发展的早期分子事件,值得进一步深入研究。

Relevant gene expression profiles changes with disruption of glioma malignant progression associated gene PASG

Objective To explore the molecular relationships between glioma malignant progression associated PASG gene and tumorigenesis and development of glioma.Methods With classical knockout techniques,7.12kb genomic DNA containing the 10th to 12th exons of PASG gene was selectively substituted by pGKneo positive screening cassette,and PASG~(-/-) mice were obtained after effective disruption of PASG gene.Morphological and gene expression changes in genomic levels were further analyzed.Results The PASG_(-/-) mice showed lower methylation level in whole genomic DNA (about 33% lower compared with PASG_( / ) mice).Large pyramidal ceils in hippocampus cortex showed abnormalities in cell morphology,number,and arrangement turbulence.Altogether 123 genes showed difference greater than 1.6 fold in gene expression array with disruption of PASG,including 61 genes down,and 62 up regulated. Conclusions As an upstream regulator,PASG can regulate expression of a series of cell proliferation, differentiation relevant downstream genes through changing methylation levels of genomic DNA.Abnormal expression of PASG leading to epigenetics changes in relevant downstream genes may be the early molecular event in tumorigenesis and development of glioma.