FOG-1-mediated recruitment of NuRD is required for cell lineage re-enforcement during haematopoiesis
FOG-1-mediated recruitment of NuRD is required for cell lineage re-enforcement during haematopoiesis
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DOI：
10.1038/emboj.2009.368
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发表时间：
2010-01-20
期刊：
影响因子：
11.4
通讯作者：
Svensson, Eric C.
中科院分区：
文献类型：
--
作者：
Gao, Zhiguang;Huang, Zan;Svensson, Eric C.
转录辅因子Friend of GATA 1（FOG-1）已被证明通过位于其N-末端的特定基序与核小体重塑和组蛋白脱乙酰酶（NuRD）复合物的亚基相互作用。为了测试FOG-1/NuRD相互作用对体内造血的重要性，我们产生了具有特异性破坏FOG-1/NuRD相互作用的突变（FOG-1（R3 K5 A））的小鼠。发现纯合子FOG-1（R3 K5 A）小鼠具有脾肿大、髓外红细胞生成、粒细胞增多和继发于巨核细胞成熟阻滞的血小板减少症。FOG-1（R3 K5 A/R3 K5 A）巨核细胞和红系祖细胞表达增加水平的GATA 2，表明FOG-1/NuRD相互作用是早期描述的“加塔开关”所必需的。此外，FOG-1/NuRD相互作用的消除导致巨核细胞和红细胞谱系中肥大细胞和嗜酸性粒细胞特异性基因的不适当表达。染色质免疫沉淀实验显示，NuRD复合物没有被适当地募集到FOG-1（R3 K5 A/R3 K5 A）巨核细胞中的肥大细胞基因启动子，这表明FOG-1/NuRD相互作用是直接抑制肥大细胞基因表达所必需的。总之，这些结果强调了FOG-1/NuRD相互作用对于体内红细胞生成和巨核细胞生成期间谱系定型的重新实施的重要性。The EMBO Journal（2010）29，457-468. doi：10.1038/doj.2009.368; 2009年12月10日在线发布
The transcriptional co-factor Friend of GATA1 (FOG-1) has been shown to interact with subunits of the nucleosome remodelling and histone deacetylase (NuRD) complex through a specific motif located at its N-terminus. To test the importance of FOG-1/NuRD interaction for haematopoiesis in vivo, we generated mice with a mutation that specifically disrupts FOG-1/NuRD interaction (FOG-1(R3K5A)). Homozygous FOG-1(R3K5A) mice were found to have splenomegaly, extramedullary erythropoiesis, granulocytosis and thrombocytopaenia secondary to a block in megakaryocyte maturation. FOG-1(R3K5A/R3K5A) megakaryocytes and erythroid progenitors expressed increased levels of GATA2, showing that FOG-1/NuRD interaction is required for the earlier described 'GATA Switch'. In addition, ablation of FOG-1/NuRD interaction led to inappropriate expression of mast cell and eosinophil-specific genes in the megakaryocyte and erythroid lineages. Chromatin immunoprecipitation experiments revealed that the NuRD complex was not properly recruited to a mast cell gene promoter in FOG-1(R3K5A/R3K5A) megakaryocytes, suggesting that FOG-1/NuRD interaction is required for the direct suppression of mast cell gene expression. Taken together, these results underscore the importance of the FOG-1/NuRD interaction for the re-enforcement of lineage commitment during erythropoiesis and megakaryopoiesis in vivo. The EMBO Journal ( 2010) 29, 457-468. doi: 10.1038/emboj.2009.368; Published online 10 December 2009