Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling
Histone demethylase KDM4A regulates adipogenic and osteogenic differentiation via epigenetic regulation of C/EBPα and canonical Wnt signaling
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组蛋白去甲基化酶 KDM4A 通过 C/EBP α 和经典 Wnt 信号传导的表观遗传调节来调节脂肪形成和成骨分化
DOI：
10.1007/s00018-019-03289-w
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发表时间：
2020-06-01
影响因子：
8
通讯作者：
Wang, Baoli
中科院分区：
文献类型：
--
作者：
Qi, Qi;Wang, Yi;Wang, Baoli
表观遗传修饰在细胞分化和发育中起核心作用。在目前的研究中，我们已经认识到赖氨酸脱甲基酶4A（KDM 4A）作为一种新的成骨细胞和脂肪细胞分化的表观遗传调节剂。Kdm 4a在原代骨髓基质细胞和已建立的基质细胞系ST 2的成骨和成脂过程中表达上调。野生型Kdm 4a的过表达促进了祖细胞的成脂分化并阻断了祖细胞的成骨分化。当进行催化死亡突变时，这种影响大大减轻。相反，在未分化的祖细胞中Kdm 4a的耗尽或失活抑制脂肪细胞的形成并促进成骨细胞的分化。机制探讨表明Kdm 4a的过表达上调了分泌型卷曲相关蛋白4（Sfrp 4）和CCAAT/增强子结合蛋白α（C/ebp α）的表达。染色质免疫沉淀实验表明，KDM 4A可直接与Sfrp 4和C/ebp α的启动子结合，去除组蛋白甲基化标记H3 K9 me 3，降低C/ebp α和Sfrp 4启动子区CpG的DNA甲基化水平。此外，Kdm 4a的过表达使经典Wnt信号转导失活。此外，通过沉默ST 2中的Sfrp 4来激活经典Wnt信号转导减弱了KDM 4A对成骨分化的抑制和对成脂分化的增强。这些数据已经确定KDM 4A作为成骨细胞和脂肪细胞分化的新型调节剂，并表明KDM 4A抑制作为治疗代谢紊乱如骨质疏松症的潜在治疗靶点。
Epigenetic modifications play a central role in cell differentiation and development. In the current study, we have recognized lysine demethylase 4A (KDM4A) as a novel epigenetic regulator of osteoblast and adipocyte differentiation. Kdm4a expression was upregulated during osteogenesis and adipogenesis of primary marrow stromal cells and established stromal ST2 line. Overexpression of wild-type Kdm4a promoted adipogenic differentiation and blocked osteogenic differentiation of the progenitor cells. This effect was largely alleviated when the catalytically dead mutation was made. Conversely, depletion or inactivation of Kdm4a in undifferentiated progenitor cells inhibited the formation of adipocytes and promoted the differentiation of osteoblasts. Mechanism explorations showed that overexpression of Kdm4a upregulated the expression of secreted frizzled-related protein 4 (Sfrp4) and CCAAT/enhancer-binding protein alpha (C/ebp alpha). Chromatin immunoprecipitation assay demonstrated that KDM4A directly bound the promoters of Sfrp4 and C/ebp alpha, removed the histone methylation mark H3K9me3, and reduced DNA methylation levels of CpG in promoter regions of C/ebp alpha and Sfrp4. Furthermore, overexpression of Kdm4a inactivated canonical Wnt signaling. Moreover, activation of canonical Wnt signaling through silencing of Sfrp4 in ST2 attenuated the inhibition of osteogenic differentiation and the enhancement of adipogenic differentiation by KDM4A. These data have identified KDM4A as a novel regulator of osteoblast and adipocyte differentiation and suggest KDM4A inhibition as a potential therapeutic target for treating metabolic disorders such as osteoporosis.