脂滴结构蛋白Plin2通过线粒体代谢调控胚胎干细胞多能性的机制研究

代谢及细胞器重塑是细胞命运转变的关键步骤。近期研究表明脂类代谢在干细胞多能性调控中起着重要作用，但其作用机制仍不清楚，脂代谢及相关细胞器的调控模式有待深入研究。我们前期工作揭示脂代谢调控因子及细胞器膜组分磷脂调控干细胞多能性的关键作用(Science Advances 2019; Stem Cells 2016)，进而发现脂代谢相关细胞器脂滴及其结构蛋白Plin2调控线粒体内脊及组蛋白乙酰化，并有助于维持多能性。由此我们推测脂滴与Plin2通过线粒体内脊及功能影响表观遗传与多能性。本项目拟在此基础上，深入研究脂滴在胚胎干细胞命运转变中的变化规律及调控模式，阐明脂滴及Plin2调控线粒体内脊和代谢的作用及机制，探索脂滴及Plin2通过线粒体代谢调控表观遗传的功能，从而在细胞器水平揭示脂代谢对干细胞多能性的调控作用及机制，为探索细胞命运转变的代谢调控提供重要思路。

Metabolic and organelle remodeling are critical for cell fate transitions. Recent studies have suggest important roles of lipid metabolism in stem cell pluripotency. However, their mechanisms of actions are still unclear, and the regulatory modes of lipid metabolism and associated organelles remain to be further studied. Our previous work revealed the critical roles of lipid metabolism regulators and phospholipids in regulating stem cell pluripotency (Science Advances 2019; Stem Cells 2016). Further, we found that lipid droplet and structural protein Plin2 regulate mitochondrial cristae and histone acetylation, facilitating pluripotency maintenance. Thus we speculated that Plin2-matained lipid droplets increase histone acetylation and promote pluripotency via mitochondrial cristae remodeling. In this project, we aim to reveal the rules and roles of lipid droplets during pluripotent stem cell fate decisions, elucidated the mechanism by which lipid droplet and Plin2 control mitochondrial cristae remodeling, and explored possible roles of lipid droplets and Plin2 on epigenetic regulation of pluripotency. This project will elucidate roles and mechanisms of lipid metabolism on stem cell pluripotency at the organelle level, and provide important insights into metabolic regulation of cell fate.