Tet1和5-hydroxymethylcytosine在肉瘤中扮演的角色及其功能

Abstract

表觀遺傳學在很多生物現象扮演重要角色，包括癌症生成和細胞分化。Ten eleven translocation (TET) 蛋白是一群染色質重塑因子，經由胞嘧啶的羥甲基化(5-hydroxymethelation of cytosine)參與在DNA去甲基化的過程中。我們以免疫染色法發現在多種肉瘤，5-hydroxymethylcytosine (5-hmC)有減少的現象。其中，分化良好型脂肪肉瘤5-hmC沒有減少而去分化型脂肪肉瘤的5-hmC常見減少。因此，我們認為胞嘧啶的羥甲基化可能和脂肪細胞的分化有關。 在3T3L1細胞株的實驗中，我們發現脂肪細胞分化的過程中，TET1和5-hmC的表現會提升。且沈默掉TET1基因會阻饒脂肪細胞的分化。利用即時聚合酶鏈鎖反應，我們發現CEBPα是TET1可能的下游目標基因，並且發現TET1經由控制CKIs調節脂肪分化。我們的結果顯示TET1的調控對於脂肪形成的過程中是重要的，而且調控CEBPα的表現量為其可能的原因。

Epigenetic changes play important roles in many biological phenomena including cancer development and cell differentiation. Ten eleven translocation (TET) proteins are a group of chromatin remodeling factors involved in the demethylation of DNA via 5-hydroxymethelation of cytosine. We found that the 5-hydroxymethelation (5-hmC) decreased in many types of sarcoma by immunohistochemistry. Especially, we discovered that 5-hmC levels were preserved in well-differentiated liposarcoma and lost in dedifferentiated liposarcoma. Therefore, we hypothesized that methylation of cytosine may be related to the differentiation of adipocyte. In the experiment using 3T3-L1 cells, we found that the expression of TET1 and the level of 5-hmC increased during differentiation. Silence of TET1 gene blocked the differentiation of adipocyte. We used real-time PCR assay found that CEBPα may be downstream targets of TET1, and TET1 regulated adipocytic differentiation through CKIs. Our results show that the regulation of TET1 is important for adipogenesis and probably through the target gene CEBPα.