Stat5a 通过结合和反式激活 Kdm6a 启动子促进棕色脂肪细胞分化和产热程序。
Stat5a promotes brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter.
机构信息
Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
Department of Pediatrics, The NO.1 Hospital of Xi'an, Xi'an, China.
出版信息
Cell Cycle. 2020 Apr;19(8):895-905. doi: 10.1080/15384101.2020.1731644. Epub 2020 Mar 24.
Previous studies reported that Stat5 promotes adipogenesis and white adipocyte differentiation. However, the role of Stat5 in brown adipocyte development is poorly understood. We found Stat5a was higher expressed in brown adipocytes than in white adipocytes, and its level was increased during the process of brown adipocyte differentiation. In addition, Stat5a expression was affected by cold stress and high-fat diet-feeding, suggesting a potential role in thermogenesis. Knockdown of Stat5a induced downregulation of brown fat specific genes (UCP1, PGC-1α, Acox-1 and Cidea), while overexpression of Stat5a did the opposite effect. What is more, bioinformatics analysis, ChIP assay and Luciferase activity assay all verified that Stat5a directly bind and transactivate Kdm6a promoter (Lysine-specific demethylase 6A). Further, we found that Stat5a overexpression promoted the expression of Kdm6a and inhibited the trimethylation of H3K27. While inhibiting of Kdm6a reversed the promoting effect of Stat5a overexpression on the expression of brown fat specific genes. Therefore, we conclude that Stat5a participated in brown adipocyte differentiation and thermogenic program through binding and transactivating the Kdm6a promoter. Stat5: Signal transducers and activators of transcription 5; BAT: brown adipose tissue; WAT; white adipose tissue; eWAT: epididymal white adipose tissue; sWAT: subcutaneous white adipose tissue; SVFs: stromal vascular fractions; UCP1: Uncoupling protein 1; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Acox-1: Peroxisomal acyl-coenzyme A oxidase 1; Cidea: Cell death activator CIDE-A; ChIP: Chromatin Immunoprecipitation; HFD: High fat diet; FBS: Fetal bovine serum; siStat5a: Stat5a siRNA; siKdm6: Kdm6a siRNA; pcDNA-Stat5a: over expression of Stat5a pcDNA3.1 vector; IgG: mouse immunoglobulin G; Kdm6a: Lysine-specific demethylase 6A; H3K27me3: trimethylated H3K27.
先前的研究表明，Stat5 促进脂肪生成和白色脂肪细胞分化。然而，Stat5 在棕色脂肪细胞发育中的作用知之甚少。我们发现 Stat5a 在棕色脂肪细胞中的表达高于白色脂肪细胞，并且在棕色脂肪细胞分化过程中其水平增加。此外，Stat5a 的表达受冷应激和高脂肪饮食喂养的影响，表明其在产热中具有潜在作用。Stat5a 的敲低诱导棕色脂肪特异性基因（UCP1、PGC-1α、Acox-1 和 Cidea）下调，而过表达 Stat5a 则产生相反的效果。更重要的是，生物信息学分析、ChIP 测定和荧光素酶活性测定均证实 Stat5a 可直接结合并反式激活 Kdm6a 启动子（赖氨酸特异性去甲基酶 6A）。此外，我们发现 Stat5a 的过表达促进了 Kdm6a 的表达并抑制了 H3K27 的三甲基化。而抑制 Kdm6a 则逆转了 Stat5a 过表达对棕色脂肪特异性基因表达的促进作用。因此，我们得出结论，Stat5a 通过结合并反式激活 Kdm6a 启动子参与棕色脂肪细胞分化和生热程序。Stat5：信号转导和转录激活因子 5；BAT：棕色脂肪组织；WAT；白色脂肪组织；eWAT：附睾白色脂肪组织；sWAT：皮下白色脂肪组织；SVFs：基质血管部分；UCP1：解偶联蛋白 1；PGC-1α：过氧化物酶体增殖物激活受体 γ 共激活因子 1-α；Acox-1：过氧化物酶体酰基辅酶 A 氧化酶 1；Cidea：细胞死亡激活因子 CIDE-A；ChIP：染色质免疫沉淀；HFD：高脂肪饮食；FBS：胎牛血清；siStat5a：Stat5a siRNA；siKdm6：Kdm6a siRNA；pcDNA-Stat5a：Stat5a pcDNA3.1 载体过表达；IgG：小鼠免疫球蛋白 G；Kdm6a：赖氨酸特异性去甲基酶 6A；H3K27me3：三甲基化 H3K27。
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