Department of Life Science, University of Seoul, Seoul, 02504, Republic of Korea.
SYSOFT R&D Center, Daegu, 42988, Republic of Korea.
Cell Death Dis. 2019 Jan 8;10(1):16. doi: 10.1038/s41419-018-1249-7.
Adipogenesis is a process which induces or represses many genes in a way to drive irreversible changes of cell phenotypes; lipid accumulation, round cell-shape, secreting many adipokines. As a master transcription factor (TF), PPARγ2 induces several target genes to orchestrate these adipogenic changes. Thus induction of Pparg2 gene is tightly regulated by many adipogenic and also anti-adipogenic factors. Four hours after the treatment of adipogenic hormones, more than fifteen TFs including glucocorticoid receptor (GR), C/EBPβ and AP-1 cooperatively bind the promoter of Pparg2 gene covering 400 bps, termed "hotspot". In this study, we show that TEA domain family transcription factor (TEAD)4 reinforces occupancy of both GR and C/EBPβ on the hotspot of Pparg2 during early adipogenesis. Our findings that TEAD4 requires GR for its expression and for the ability to bind its own promoter and the hotspot region of Pparg2 gene indicate that GR is a common component of two positive circuits, which regulates the expression of both Tead4 and Pparg2. Wnt3a disrupts these mutually related positive circuits by limiting the nuclear location of GR in a β-catenin dependent manner. The antagonistic effects of β-catenin extend to cytoskeletal remodeling during the early phase of adipogenesis. GR is necessary for the rearrangements of both cytoskeleton and chromatin of Pparg2, whereas Wnt3a inhibits both processes in a β-catenin-dependent manner. Our results suggest that hotspot formation during early adipogenesis is related to cytoskeletal remodeling, which is regulated by the antagonistic action of GR and β-catenin, and that Wnt3a reinforces β-catenin function.
脂肪生成是一个诱导或抑制许多基因的过程，以驱动细胞表型的不可逆变化；脂质积累、圆形细胞形状、分泌许多脂肪因子。作为主要转录因子（TF），PPARγ2 诱导几个靶基因来协调这些脂肪生成变化。因此，Pparg2 基因的诱导受到许多脂肪生成和抗脂肪生成因子的严格调控。在脂肪生成激素处理 4 小时后，包括糖皮质激素受体（GR）、C/EBPβ 和 AP-1 在内的超过 15 个 TF 共同结合 Pparg2 基因启动子的 400bp 区域，称为“热点”。在这项研究中，我们表明 TEA 结构域家族转录因子（TEAD）4 在早期脂肪生成过程中增强了 GR 和 C/EBPβ 在 Pparg2 热点上的占据。我们的发现表明，TEAD4 需要 GR 来表达，并具有结合其自身启动子和 Pparg2 基因热点区域的能力，表明 GR 是两个正回路的共同组成部分，调节 Tead4 和 Pparg2 的表达。Wnt3a 通过依赖 β-连环蛋白的方式限制 GR 的核定位，破坏了这些相互关联的正回路。β-连环蛋白的拮抗作用在脂肪生成的早期阶段延伸到细胞骨架重塑。GR 对于 Pparg2 的细胞骨架和染色质重排都是必需的，而 Wnt3a 以依赖 β-连环蛋白的方式抑制这两个过程。我们的结果表明，早期脂肪生成过程中的热点形成与细胞骨架重塑有关，这是由 GR 和 β-连环蛋白的拮抗作用调节的，而 Wnt3a 增强了 β-连环蛋白的功能。
