Gene Regulation, Stem Cells and Cancer Program, Center for Genomic Regulation, and Pompeu Fabra University, Barcelona, Spain.
Mol Cell. 2012 Oct 26;48(2):266-76. doi: 10.1016/j.molcel.2012.08.007. Epub 2012 Sep 13.
The methylcytosine hydroxylase Tet2 has been implicated in hematopoietic differentiation and the formation of myeloid malignancies when mutated. An ideal system to study the role of Tet2 in myelopoeisis is CEBPα-induced transdifferentiation of pre-B cells into macrophages. Here we found that CEBPα binds to upstream regions of Tet2 and that the gene becomes activated. Tet2 knockdowns impaired the upregulation of macrophage markers as well as phagocytic capacity, suggesting that the enzyme is required for both early and late stage myeloid differentiation. A slightly weaker effect was seen in primary cells with a Tet2 ablation. Expression arrays of transdifferentiating cells with Tet2 knockdowns permitted the identification of a small subset of myeloid genes whose upregulation was blunted. Activation of these target genes was accompanied by rapid increases of promoter hydroxy-methylation. Our observations indicate that Tet2 helps CEBPα rapidly derepress myeloid genes during the conversion of pre-B cells into macrophages.
Tet2 是一种甲基胞嘧啶羟化酶，当发生突变时，它与造血分化和髓系恶性肿瘤的形成有关。研究 Tet2 在髓系生成中的作用的理想系统是 CEBPα 诱导前 B 细胞向巨噬细胞的转分化。在这里，我们发现 CEBPα 结合到 Tet2 的上游区域，并且该基因被激活。Tet2 敲低会损害巨噬细胞标志物的上调以及吞噬能力，这表明该酶对于早期和晚期髓系分化都是必需的。在 Tet2 缺失的原代细胞中观察到稍弱的效果。用 Tet2 敲低转分化细胞的表达谱允许鉴定一小部分髓样基因，其上调受到抑制。这些靶基因的激活伴随着启动子羟甲基化的快速增加。我们的观察表明，Tet2 有助于 CEBPα 在将前 B 细胞转化为巨噬细胞的过程中快速解除对髓样基因的抑制。
