间充质干细胞(mesenchymal stem cell，MSC)在体外长期培养过程中会发生自发转化，转化后的MSC在移植到裸鼠体内后具有形成纤维肉瘤和骨肉瘤的能力。本课题组及国外研究均发现：由表观遗传学修饰模式改变引起的p16INK4a基因的稳固沉默在MSC自发转化中起重要作用。为分析p16INK4a基因的表观遗传修饰模式发生改变的机制，本项目以表观遗传修饰调控蛋白Snf5为切入点，采用RNAi和外源性表达的方法分析Snf5在p16INK4a基因的可调控抑制和稳固沉默模式相互转换中的作用；通过高通量芯片技术分析该机制是否同时参与其它抑癌基因的表观遗传学沉默；并进一步探讨恢复Snf5表达能否解除这种稳固沉默模式，甚至逆转自发转化的过程。该研究能为MSC自发转化和肿瘤发生提供表观遗传学理论依据，在肿瘤的诊断和治疗以及转化医学中具有重要的科学意义和潜在的应用价值。

Accumulating data have shown that mesenchymal stem cells (MSCs) from various species frequently undergo spontaneous transformation after long-term culture. The transformed MSCs demonstrate some characteristics of malignant cells and can form fibrosarcoma and osteosarcoma when injected into immunodeficient mice. Recent studies have revealed that p16INK4a is silenced by the epigenetic modifications in transformed MSCs, but the epigenetic mechanisms in the stable silence of p16INK4a gene remain unclear. This study is designed to determine the role of Snf5, an epigenetic regulatory factor, during the spontaneous transformation of MSCs by RNA interference and exogenous expression, especially in the switch between the reversible suppression and stable silence of p16INK4a gene by bisulphate sequencing and chromatin immunoprecipitation assay. The epigenomic modifications controlled by these regulatory mechanisms will be evaluated by the high-throughput microarrays. Furthermore, the meanings of relieving the stable silence will be verified by exogenous expression of Snf5. Our research could reveal epigenetic mechanism in the spontaneous transformation of MSCs and tumorgenesis. The study will be of great scientific significance in the diagnosis and treatment of tumors.