α-synuclein A53T转基因帕金森小鼠模型DNA甲基化研究
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摘要
帕金森病(Parkinson's disease, PD),又叫震颤麻痹(paralysis agitans),是中老年人群中一种常见的神经系统变性疾病,随着人口的老龄化,其发病率呈逐渐上升趋势,大于65岁人群的发病率约为1%,成为继阿尔茨海默病之后的第二大退行性疾病。DNA甲基化是哺乳动物研究最深入的表观遗传学改变,它与疾病的关系已逐渐成为医学研究的新热点之一。研究发现,DNA甲基化水平异常在PD发病过程中起重要作用,但目前的研究多集中在检测某一个或几个基因启动子区域甲基化改变,尚缺乏在全基因组水平上的甲基化改变研究。
目的：探讨a-synuclein A53T转基因PD小鼠模型基因组水平的甲基化改变,了解发生甲基化改变基因涉及的通路。寻找PD致病位点PARK1-18中哪些基因发生了甲基化改变,研究这些基因的转录水平改变。
方法：解剖获得转基因PD小鼠模型和正常对照小鼠脑组织黑质,提取基因组DNA和RNA。利用DNA甲基化芯片(Roche Nimbleg)从全基因组水平寻找存在甲基化差异的基因并进行基因通路分析；重亚硫酸盐测序(Bisulfite PCR Sequencing, BSP)技术研究目的基因甲基化水平；实时荧光定量PCR (RT-PCR)研究目的基因的转录改变。
结果：DNA甲基化芯片共比对了全基因组12535个基因的启动子区,两组小鼠存在甲基化水平差异的基因共有3572个,其中转基因组较对照组甲基化水平降低的基因有2031个,甲基化水平升高的有1541个。通路及聚类分析显示甲基化差异基因涉及的通路包括SNARE介导的囊泡转运,甘氨酸、丝氨酸、苏氨酸代谢,内质网蛋白合成,P53信号通路,泛素蛋白酶通路,WNT信号通路,NOTCH信号通路等在内的二十余条信号通路。其中,SNARE介导的囊泡转运,泛素蛋白酶通路,WNT信号通路与PD关系最密切。差异基因中,RARK5(Uchl1)和PARK15(Fbxo7)启动子在转基因小鼠中甲基化水平明显下降,有统计学意义(Uchl1p=0.012*；Fbxo7p=0.002*). Uchll基因在转基因小鼠黑质部位表达明显升高(p=0.017*),Fbxo7基因在两组小鼠黑质表达无明显差异(p=0.472)。
结论：1.在国内外首次利用α-synuclein A53T转基因小鼠PD模型进行DNA甲基化研究。α-synuclein A53T转基因小鼠PD模型黑质部位DNA存在甲基化修饰异常。异常基因涉及多条信号通路
2.证实甲基化免疫共沉淀技术结合DNA芯片技术(MeDIP-Chip)是在基因组水平上筛选存在甲基化修饰异常基因的有效方法。α-synuclein A53T转基因小鼠PD模型黑质部位筛选出的PD相关甲基化修饰异常的基因可作为下一步研究的靶基因
3.α-synuclein A53T转基因小鼠PD模型黑质部位PARK5(Uchl1)和PARK15(Fbxo7)基因存在低甲基化,且Uchl1基因转录水平明显升高
4.Uchl1基因表达受启动子区CpG岛甲基化水平调控
Parkinson's disease (PD), also know as paralysis agitans, is a common neurodegenerative disease of old people. The prevalence is more than1%of the population over65years old, and it has become the second top neurodegenerative disease after Alzheimer's disease. With the aging of population, the incidence rate shows an increasing trend. DNA methylation is the most important and deeply understood epigenetic modification in mammal. Mounting studies have shown a pivotal role that methylation plays in PD etiology and development. However, those researches mainly focus on one or several special genes and test their methylation status at promoter regions, lacking of genomic level studies.
Objective To test the methylation status alternations of a-synuclein A53T transgenic PD mouse model at genomic level and summary the involved signal pathways. Investigate methylation changes among the PD causative loci PARK1-18, and study those genes' expression level.
Methods Extract DNA and RNA from substantial nigral of24transgenic and24normal control mice. Use5-methylcytosine antibody immunoprecipitation method combines with high-density microarray hybridization (MeDIP-Chip) to depict the global changes in DNA methylation between the two groups, and analysize the pathways involved in the altered genes. Use Bisulfite Sequencing PCR (BSP) technology to test the methylation levels of interesting genes. Utilize RT-PCR method to study gene's expression level.
Results The DNA Methylation Chip scanned12535genes'promoter regions in the two groups, and found3572genes had methylation alternations. Compare to normal control, transgenic mice had2031genes with hypomethylation status, and1541genes had increased methylation level. Pathway analysis showed that the involved genes relevant to over20signal pathways, including glycine, serine and threonine metabolism, proteasome, SNARE interactions in vesicular transport, P53signaling pathway, ubiquitin mediated proteolysis, WNT signaling pathway, NOTCH signaling pathway, etc. Among them, SNARE interactions in vesicular transport, ubiquitin mediated proteolysis and WNT signaling pathway were considered as closely related to PD. BSP result showed PARK5(Uchll) and PARK15(Fbxo7) were both with significant hypomethylation status in transgenic mice, with Uchll p=0.012*; Fbxo7p=0.002*. Uchll gene expressed significantly increased in transgenic mice (p=0.017*), but Fbxo7had no different expression level between the two groups (p=0.472).
Conclusions
1. This is the first research that uses a-synuclein A53T transgenic PD mice model to study DNA methylation alternations wordwild. They have abnormal methylation status, and several signaling pathways are involved
2. MeDIP-Chip is an effective method for genome-wide analysis of DNA methylation changes. The involved genes can be further studied in future reaearches
3. PARK5(Uchll) and PARK15(Fbxo7) are both significant hypomethylation in transgenic mice. Uchll gene's expression level is significantly increased in transgenic mice
4. The transcription level of PARK5(Uchll) can be regulated by the CpG island methylation status of its promotor region
目的：探讨a-synuclein A53T转基因PD小鼠模型基因组水平的甲基化改变,了解发生甲基化改变基因涉及的通路。寻找PD致病位点PARK1-18中哪些基因发生了甲基化改变,研究这些基因的转录水平改变。
方法：解剖获得转基因PD小鼠模型和正常对照小鼠脑组织黑质,提取基因组DNA和RNA。利用DNA甲基化芯片(Roche Nimbleg)从全基因组水平寻找存在甲基化差异的基因并进行基因通路分析；重亚硫酸盐测序(Bisulfite PCR Sequencing, BSP)技术研究目的基因甲基化水平；实时荧光定量PCR (RT-PCR)研究目的基因的转录改变。
结果：DNA甲基化芯片共比对了全基因组12535个基因的启动子区,两组小鼠存在甲基化水平差异的基因共有3572个,其中转基因组较对照组甲基化水平降低的基因有2031个,甲基化水平升高的有1541个。通路及聚类分析显示甲基化差异基因涉及的通路包括SNARE介导的囊泡转运,甘氨酸、丝氨酸、苏氨酸代谢,内质网蛋白合成,P53信号通路,泛素蛋白酶通路,WNT信号通路,NOTCH信号通路等在内的二十余条信号通路。其中,SNARE介导的囊泡转运,泛素蛋白酶通路,WNT信号通路与PD关系最密切。差异基因中,RARK5(Uchl1)和PARK15(Fbxo7)启动子在转基因小鼠中甲基化水平明显下降,有统计学意义(Uchl1p=0.012*；Fbxo7p=0.002*). Uchll基因在转基因小鼠黑质部位表达明显升高(p=0.017*),Fbxo7基因在两组小鼠黑质表达无明显差异(p=0.472)。
结论：1.在国内外首次利用α-synuclein A53T转基因小鼠PD模型进行DNA甲基化研究。α-synuclein A53T转基因小鼠PD模型黑质部位DNA存在甲基化修饰异常。异常基因涉及多条信号通路
2.证实甲基化免疫共沉淀技术结合DNA芯片技术(MeDIP-Chip)是在基因组水平上筛选存在甲基化修饰异常基因的有效方法。α-synuclein A53T转基因小鼠PD模型黑质部位筛选出的PD相关甲基化修饰异常的基因可作为下一步研究的靶基因
3.α-synuclein A53T转基因小鼠PD模型黑质部位PARK5(Uchl1)和PARK15(Fbxo7)基因存在低甲基化,且Uchl1基因转录水平明显升高
4.Uchl1基因表达受启动子区CpG岛甲基化水平调控
Parkinson's disease (PD), also know as paralysis agitans, is a common neurodegenerative disease of old people. The prevalence is more than1%of the population over65years old, and it has become the second top neurodegenerative disease after Alzheimer's disease. With the aging of population, the incidence rate shows an increasing trend. DNA methylation is the most important and deeply understood epigenetic modification in mammal. Mounting studies have shown a pivotal role that methylation plays in PD etiology and development. However, those researches mainly focus on one or several special genes and test their methylation status at promoter regions, lacking of genomic level studies.
Objective To test the methylation status alternations of a-synuclein A53T transgenic PD mouse model at genomic level and summary the involved signal pathways. Investigate methylation changes among the PD causative loci PARK1-18, and study those genes' expression level.
Methods Extract DNA and RNA from substantial nigral of24transgenic and24normal control mice. Use5-methylcytosine antibody immunoprecipitation method combines with high-density microarray hybridization (MeDIP-Chip) to depict the global changes in DNA methylation between the two groups, and analysize the pathways involved in the altered genes. Use Bisulfite Sequencing PCR (BSP) technology to test the methylation levels of interesting genes. Utilize RT-PCR method to study gene's expression level.
Results The DNA Methylation Chip scanned12535genes'promoter regions in the two groups, and found3572genes had methylation alternations. Compare to normal control, transgenic mice had2031genes with hypomethylation status, and1541genes had increased methylation level. Pathway analysis showed that the involved genes relevant to over20signal pathways, including glycine, serine and threonine metabolism, proteasome, SNARE interactions in vesicular transport, P53signaling pathway, ubiquitin mediated proteolysis, WNT signaling pathway, NOTCH signaling pathway, etc. Among them, SNARE interactions in vesicular transport, ubiquitin mediated proteolysis and WNT signaling pathway were considered as closely related to PD. BSP result showed PARK5(Uchll) and PARK15(Fbxo7) were both with significant hypomethylation status in transgenic mice, with Uchll p=0.012*; Fbxo7p=0.002*. Uchll gene expressed significantly increased in transgenic mice (p=0.017*), but Fbxo7had no different expression level between the two groups (p=0.472).
Conclusions
1. This is the first research that uses a-synuclein A53T transgenic PD mice model to study DNA methylation alternations wordwild. They have abnormal methylation status, and several signaling pathways are involved
2. MeDIP-Chip is an effective method for genome-wide analysis of DNA methylation changes. The involved genes can be further studied in future reaearches
3. PARK5(Uchll) and PARK15(Fbxo7) are both significant hypomethylation in transgenic mice. Uchll gene's expression level is significantly increased in transgenic mice
4. The transcription level of PARK5(Uchll) can be regulated by the CpG island methylation status of its promotor region
引文
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