Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells.
Tet2 facilitates the derepression of myeloid target genes during CEBPα-induced transdifferentiation of pre-B cells.
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DOI：
10.1016/j.molcel.2012.08.007
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发表时间：
2012-10-26
期刊：
影响因子：
16
通讯作者：
Graf, Thomas
中科院分区：
文献类型：
--
作者：
Kallin, Eric M.;Rodriguez-Ubreva, Javier;Christensen, Jesper;Cimmino, Luisa;Aifantis, Iannis;Helin, Kristian;Ballestar, Esteban;Graf, Thomas
甲基胞嘧啶羟化酶 Tet2 突变后与造血分化和骨髓恶性肿瘤的形成有关。研究Tet2在骨髓生成中的作用的理想系统是C/EBP诱导的前B细胞转分化为巨噬细胞。在这里，我们发现C/EBPα与Tet2的上游区域结合并且该基因被激活。 Tet2 敲除损害了巨噬细胞标记物的上调以及吞噬能力，表明该酶是早期和晚期骨髓分化所必需的。在 Tet2 消融的原代细胞中观察到效果稍弱。敲低 Tet2 的转分化细胞的表达阵列允许鉴定一小部分上调被削弱的骨髓基因。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，在前B细胞转化为巨噬细胞的过程中，Tet2帮助C/EBP快速解除对骨髓基因的抑制。
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 C/EBPa induced transdifferentiation of pre-B cells into macrophages. Here we found that C/EBPa 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 C/EBPa rapidly de-repress myeloid genes during the conversion of pre-B cells into macrophages.
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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影响因子：
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作者：
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