Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, 04103 Leipzig, Germany; LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103 Leipzig, Germany.
Leipzig University Medical Center, Integrated Research and Treatment Centre Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany.
Biochim Biophys Acta Mol Basis Dis. 2017 Jul;1863(7):1709-1717. doi: 10.1016/j.bbadis.2017.05.011. Epub 2017 May 10.
Differentiation of adipocytes is a highly regulated process modulated by multiple transcriptional co-activators and co-repressors. JMJD1C belongs to the family of jumonji C (jmjC) domain-containing histone demethylases and was originally described as a ligand-dependent co-activator of thyroid hormone and androgen receptors. Here, we explored the potential role of Jmjd1c in white adipocyte differentiation. To investigate the relevance of Jmjd1c in adipogenesis, murine 3T3-L1 preadipocyte cells with transient knock-down of Jmjd1c (3T3_Jmjd1c) were generated. Depletion of Jmjd1c led to the formation of smaller lipid droplets, reduced accumulation of triglycerides and maintenance of a more fibroblast-like morphology after adipocyte differentiation. Concomitantly, insulin stimulated uptake of glucose and fatty acids was significantly reduced in 3T3_Jmjd1c adipocytes. In line with these observations we detected lower expression of key genes associated with lipid droplet formation (Plin1, Plin4, Cidea) and uptake of glucose and fatty acids (Glut4, Fatp1, Fatp4, Aqp7) respectively. Finally, we demonstrate that depletion of Jmjd1c interferes with mitotic clonal expansion (MCE), increases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at promotor regions of adipogenic transcription factors (C/EBPs and PPARγ) and leads to reduced induction of these key regulators. In conclusion, we have identified Jmjd1c as a modulator of adipogenesis. Our data suggest that Jmjd1c may participate in MCE and the activation of the adipogenic transcription program during the induction phase of adipocyte differentiation in 3T3-L1 cells.
脂肪细胞的分化是一个受多种转录共激活因子和共抑制因子调节的高度调控过程。JMJD1C 属于 jumonji C（jmjC）结构域含有组蛋白去甲基酶家族，最初被描述为甲状腺激素和雄激素受体的配体依赖性共激活因子。在这里，我们探讨了 Jmjd1c 在白色脂肪细胞分化中的潜在作用。为了研究 Jmjd1c 在脂肪生成中的相关性，我们生成了 Jmjd1c 瞬时敲低的小鼠 3T3-L1 前脂肪细胞（3T3_Jmjd1c）。Jmjd1c 的耗竭导致更小的脂滴形成，甘油三酯积累减少，脂肪细胞分化后维持更类似成纤维细胞的形态。同时，胰岛素刺激的葡萄糖和脂肪酸摄取在 3T3_Jmjd1c 脂肪细胞中显著降低。与这些观察结果一致，我们检测到与脂滴形成（Plin1、Plin4、Cidea）和葡萄糖及脂肪酸摄取（Glut4、Fatp1、Fatp4、Aqp7）相关的关键基因表达水平降低。最后，我们证明 Jmjd1c 的耗竭会干扰有丝分裂克隆扩张（MCE），增加脂肪生成转录因子（C/EBPs 和 PPARγ）启动子区域的 H3K9me2（组蛋白 H3 赖氨酸 9 的二甲基化）水平，并导致这些关键调节因子的诱导减少。总之，我们已经确定 Jmjd1c 是脂肪生成的调节剂。我们的数据表明，Jmjd1c 可能参与 3T3-L1 细胞脂肪细胞分化诱导阶段的 MCE 和脂肪生成转录程序的激活。
