DNA结合蛋白Ets1调控脂肪细胞米色化的功能和机制研究

米色脂肪含量降低是肥胖症发生的重要原因，如何激活脂肪米色化已成为肥胖症防治中的研究热点。表观遗传修饰是机体调控米色化的重要机制。通过ATAC-seq，我们绘制了小鼠白色、米色和棕色脂肪的染色质开放图谱，发现Ets1是调控米色化的新表观修饰因子。具体表现为：Ets1的表达在米色脂肪中上调，而在肥胖小鼠和肥胖人群中下调；脂肪组织Ets1敲除鼠米色化能力降低，过表达Ets1则促进米色脂肪细胞分化；通过ChIP-seq进行机制研究发现，Ets1通过促进Ndufb5等线粒体蛋白的转录调控线粒体功能。有趣的是，Ets1并不依赖于其转录活性，而是作为表观修饰因子发挥这一作用，但机制尚不明确。本研究旨在分子、细胞和动物水平，借助表观遗传研究方法及脂肪组织特异性敲除、敲入鼠，深入研究Ets1调控脂肪米色化的功能及机制。本研究不仅有助于阐明调控脂肪细胞米色化的分子机制，还将对改善肥胖、控制体重提供新的思路。

The weakened beige ability of adipocytes is a leading cause of obesity, hence activating beige process has become a research hotspot in the prevention and treatment of obesity and the consequent metabolic disorder. Epigenetic modification is an important mechanism for regulating beige adipose activity. In the previous study, we plotted the atlas of chromatin accessibility of white, beige and brown adipocytes, and results suggested that the DNA binding protein Ets1 might be a new epigenetic modulator that regulate beige ability in adipose tissue. The expression level of Ets1 was up-regulated during the beige process of adipocytes, and down-regulated in the obese mice and people. The beige activity of adipose specific Ets1 knockout mice was reduced, while overexpression of Ets1 in primary SVF adipocytes promoted the differentiation of beige fat. Through the mechanism study of ChIP-seq, Ets1 was found to regulate the mitochondrial bio-functions by promoting the transcription of mitochondrial proteins such as Ndufb5. Interestingly, preliminary data suggest that Ets1 modulate beige process as an epigenetic regulator rather than a transcription factor, but the mechanism is yet unclear. By means of epigenetic methods and adipose specific knock-out/knock-in mice, the purpose of this study is to discover the function and mechanism of Ets1 in modulating adipocyte beige process. This study will not only elucidate the molecular mechanism of regulating adipocytes beige process, but also provide new ideas for obesity treatment and body weight control.