Department of Biological Sciences, College of Natural Science, Inha University, 100 Inha-ro, Michuhol-gu, Incheon, 22212, Korea.
Sci Rep. 2020 Feb 20;10(1):3050. doi: 10.1038/s41598-020-60049-8.
The coordinated and sequential actions of lineage-specific transcription factors and epigenetic regulators are essential for the initiation and maintenance of cellular differentiation. We here report KDM4D histone demethylase as a key regulator of adipogenesis in C3H10T1/2 mesenchymal stem cells. The depletion of KDM4D results in impaired differentiation, which can be rescued by exogenous KDM4D, PPARγ, and C/EBPα, but not by C/EBPβ. In addition, KDM4D interacts physically and functionally with both NFIB and MLL1 complex to regulate C/EBPα and PPARγ expression upon adipogenic hormonal induction. Although KDM4D is dispensable for the binding of both NFIB and MLL1 complex to the target promoters, the demethylation of tri-methylated H3K9 by KDM4D is required for NFIB and MLL1 complex to deposit tri-methylated H3K4 and activate PPARγ and C/EBPα expression. Taken together, our data provide a molecular framework for lineage-specific transcription factor and histone modifiers to cooperate in adipogenic differentiation, in which KDM4D removes repressive histone marks at genes with a bivalent chromatin domain and allows NFIB and MLL1 complex to promote the expression of key adipogenic regulators.
谱系特异性转录因子和表观遗传调节剂的协调和顺序作用对于细胞分化的起始和维持至关重要。我们在这里报告 KDM4D 组蛋白去甲基酶是 C3H10T1/2 间充质干细胞脂肪生成中的关键调节剂。KDM4D 的耗竭导致分化受损，外源性 KDM4D、PPARγ 和 C/EBPα 可以挽救这种情况，但 C/EBPβ 不行。此外，KDM4D 与 NFIB 和 MLL1 复合物在物理和功能上相互作用，以调节 C/EBPα 和 PPARγ 的表达，在诱导脂肪生成激素时。虽然 KDM4D 对于 NFIB 和 MLL1 复合物与靶启动子的结合是可有可无的，但 KDM4D 对三甲基化 H3K9 的去甲基化对于 NFIB 和 MLL1 复合物沉积三甲基化 H3K4 和激活 PPARγ 和 C/EBPα 的表达是必需的。总之，我们的数据提供了一个分子框架，用于谱系特异性转录因子和组蛋白修饰剂在脂肪生成分化中合作，其中 KDM4D 在具有双价染色质结构域的基因上去除抑制性组蛋白标记，并允许 NFIB 和 MLL1 复合物促进关键脂肪生成调节剂的表达。
