Karner Courtney M, Esen Emel, Chen Jiakun, Hsu Fong-Fu, Turk John, Long Fanxin
From the Department of Orthopaedic Surgery.
From the Department of Orthopaedic Surgery, Division of Biology and Biomedical Sciences.
J Biol Chem. 2016 Jun 17;291(25):13028-39. doi: 10.1074/jbc.M115.708578. Epub 2016 Apr 20.
Developmental signals in metazoans play critical roles in inducing cell differentiation from multipotent progenitors. The existing paradigm posits that the signals operate directly through their downstream transcription factors to activate expression of cell type-specific genes, which are the hallmark of cell identity. We have investigated the mechanism through which Wnt signaling induces osteoblast differentiation in an osteoblast-adipocyte bipotent progenitor cell line. Unexpectedly, Wnt3a acutely suppresses the expression of a large number of genes while inducing osteoblast differentiation. The suppressed genes include Pparg and Cebpa, which encode adipocyte-specifying transcription factors and suppression of which is sufficient to induce osteoblast differentiation. The large scale gene suppression induced by Wnt3a corresponds to a global decrease in histone acetylation, an epigenetic modification that is associated with gene activation. Mechanistically, Wnt3a does not alter histone acetyltransferase or deacetylase activities but, rather, decreases the level of acetyl-CoA in the nucleus. The Wnt-induced decrease in histone acetylation is independent of β-catenin signaling but, rather, correlates with suppression of glucose metabolism in the tricarboxylic acid cycle. Functionally, preventing histone deacetylation by increasing nucleocytoplasmic acetyl-CoA levels impairs Wnt3a-induced osteoblast differentiation. Thus, Wnt signaling induces osteoblast differentiation in part through histone deacetylation and epigenetic suppression of an alternative cell fate.
后生动物中的发育信号在诱导多能祖细胞分化为特定细胞类型的过程中发挥着关键作用。现有的范例认为，这些信号直接通过其下游转录因子发挥作用，以激活细胞类型特异性基因的表达，这些基因是细胞身份的标志。我们研究了Wnt信号通路在成骨细胞-脂肪细胞双能祖细胞系中诱导成骨细胞分化的机制。出乎意料的是，Wnt3a在诱导成骨细胞分化的同时，会急性抑制大量基因的表达。被抑制的基因包括Pparg和Cebpa，它们编码脂肪细胞特异性转录因子，抑制这些基因足以诱导成骨细胞分化。Wnt3a诱导的大规模基因抑制对应于组蛋白乙酰化的整体下降，组蛋白乙酰化是一种与基因激活相关的表观遗传修饰。从机制上讲，Wnt3a不会改变组蛋白乙酰转移酶或去乙酰化酶的活性，而是降低细胞核中乙酰辅酶A的水平。Wnt诱导的组蛋白乙酰化减少与β-连环蛋白信号无关，而是与三羧酸循环中葡萄糖代谢的抑制相关。在功能上，通过增加核质乙酰辅酶A水平来防止组蛋白去乙酰化会损害Wnt3a诱导的成骨细胞分化。因此，Wnt信号通路部分通过组蛋白去乙酰化和对另一种细胞命运的表观遗传抑制来诱导成骨细胞分化。
