细胞命运决定中不同蛋白水平OCT4A差异性调控CITED2转录的机制研究

干性转录因子OCT4A在多能干细胞和肿瘤干细胞的干性维持与体细胞重编程中均发挥关键作用。研究表明OCT4A的功能与其在细胞中的蛋白水平密切相关，但其分子机制尚未阐明。申请人通过前期研究和文献数据挖掘以及生物信息学预测发现，在多能干细胞和肿瘤细胞中，OCT4A在转录水平上差异化调控CITED2基因的表达。本项目拟在前期工作基础上进一步在肿瘤细胞和多能干细胞命运决定过程中，研究不同蛋白水平OCT4A通过与相关调控区域内多个顺式作用元件的多样化互作差异化调控CITED2基因转录从而参与细胞命运决定的分子机制。本项目的开展将加深对OCT4A调控细胞命运决定作用机制的理解，为实现细胞命运的精准调控及肿瘤干预提供新的理论依据。

The pluripotency factor OCT4A plays key roles in stemness maintaining of pluripotent stem cells and cancer stem cells, and in somatic cell reprogramming. It has been reported that the functions of OCT4A are closely associated with its protein levels, however, the molecular mechanisms underlying the “protein level-dependent functional diversity of OCT4A” remain ill-defined. By comparing transcript profiling data of OCT4A knockout HeLa cells, retinoic acid-induced differentiation of NCCIT cells, OCT4A knockdown or CDK1 inhibitor-mediated differentiation of H1 cells, and performing in silico transcription factor binding predictions, we identified CITED2, a critical regulatory gene in both pluripotent stem cells and cancer cells, was identified as a potential target of OCT4A in pluripotent stem cell and cancer cell-based cell fate determination. In the present study, we aim to further explore how protein level-dependent interactions of OCT4A with multiple octamer motifs within and around the CITED2 gene differentially regulate CITED2 transcription and then participate in cell fate determination. This study will elucidate the molecular mechanisms of “protein level-dependent functional diversity of OCT4A” in multiple contexts of cell fate determination and add novel theoretical evidence to the manipulation of cell fate and the intervention of tumors.