转录因子BCL11A调控磷脂合成参与UVB诱导角质形成细胞自噬的机制研究

自噬是饥饿、辐射应激条件下细胞生存的关键途径，但UVB辐照诱导细胞自噬分子机制仍有待深入探索。前期研究发现BCL11A在受照的HaCaT细胞中表达下调，过表达BCL11A则加剧细胞死亡并且抑制自噬；经转录组测序发现过表达BCL11A后差异基因富集于磷脂合成通路，并预测靶基因为磷脂合成关键酶PCYT1A和PCYT2。由于磷脂是自噬体膜的重要组分，我们推断BCL11A通过转录调控磷脂合成参与UVB介导的细胞自噬。本项目拟利用UVB辐照的细胞和小鼠模型，明确受照后BCL11A的表达变化；调控BCL11A表达，体外实验分析细胞损伤以及自噬水平的变化，利用ChIP等实验确定BCL11A的靶基因，经代谢组学等分析磷脂合成的变化并利用活细胞成像等技术分析BCL11A对自噬体形成的影响。该研究将阐明BCL11A调控磷脂合成参与UVB诱导细胞自噬的分子机制，并为紫外线的防护和治疗提供理论依据和策略。

Autophagy is a key pathway for cell survival and adaptation under starvation and radiation. However, the molecular mechanism of autophagy induced by UVB irradiation remains to be further explored. Previous studies found that the expression of BCL11A was down-regulated in HaCaT cells irradiated by UVB, and overexpression accelerated the death of those exposed cells. RNA-seq showed that differential genes were enriched in phospholipid synthesis pathway after overexpression of BCL11A in HaCaT cells, and the key enzymes PCYT1A and PCYT2 in this process were predicted to be the target genes of BCL11A. Since phospholipids are an important component of autophagy membrane, we infer that BCL11A is involved in UVB mediated autophagy through transcriptional regulation of phospholipid synthesis. This project is intended to establish UVB irradiated cell and mouse models to clarify the changes in the expression of BCL11A after irradiation. With the expression of BCL11A up or down regulated, cell damage and autophagy level will be analyzed. To evaluate the transcriptional regulation of phospholipid synthesis by BCL11a, the target genes will be determined by ChIP and other experiments and the changes in phospholipid synthesis analyzed by metabolomics. The effects of BCL11A on autophagy formation will be analyzed by living cell imaging and other technologies. This study will clarify the molecular mechanism that BCL11A regulates phospholipid synthesis and participates in UVB induced autophagy, and provide theoretical basis and strategies for UV protection and treatment.