Eos, MITF, and PU.1 recruit corepressors to osteoclast-specific genes in committed myeloid progenitors
Eos, MITF, and PU.1 recruit corepressors to osteoclast-specific genes in committed myeloid progenitors
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DOI：
10.1128/mcb.01839-06
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发表时间：
2007-06-01
影响因子：
5.3
通讯作者：
Ostrowski, Michael C.
中科院分区：
文献类型：
--
作者：
Hu, Rong;Sharma, Sudarshana M.;Ostrowski, Michael C.
转录因子 MITF 和 PU.1 在破骨细胞分化过程中协同增加组织蛋白酶 K (Ctsk) 和酸性磷酸酶 5 (Acp5) 等靶基因的表达。我们发现这些因子还可以抑制能够形成巨噬细胞或破骨细胞的定型骨髓前体中靶基因的转录。 MITF 和 PU.1 与锌指蛋白 Eos（Ikaros 家族成员）的直接相互作用对于抑制 Ctsk 和 Acp5 是必要的。 Eos 在靶基因启动子处与 MITF 和 PU.1 形成复合物，并通过招募辅阻遏物 CtBP（C 端结合蛋白）和 Sin3A 来抑制转录，但在破骨细胞分化过程中，Eos 与 Ctsk 和 Acp5 启动子的关联显着减少。随后，MITF 和 PU.1 为这些靶基因招募共激活子，从而导致靶基因的稳健表达。骨髓源性前体中 Eos 的过度表达会破坏破骨细胞分化并选择性抑制 MITF/PU.1 靶标的转录，而 Eos 的小干扰 RNA 敲低会导致 Ctsk 和 Acp5 的基础表达增加。这项工作提供了一种机制，可以解释定型骨髓祖细胞中 MITF 和 PU.1 活性的调节，然后破骨细胞分化开始响应适当的细胞外信号。
Transcription factors MITF and PU.1 collaborate to increase expression of target genes like cathepsin K (Ctsk) and acid phosphatase 5 (Acp5) during osteoclast differentiation. We show that these factors can also repress transcription of target genes in committed myeloid precursors capable of forming either macrophages or osteoclasts. The direct interaction of MITF and PU.1 with the zinc finger protein Eos, an Ikaros family member, was necessary for repression of Ctsk and Acp5. Eos formed a complex with MITF and PU.1 at target gene promoters and suppressed transcription through recruitment of corepressors CtBP (C-terminal binding protein) and Sin3A, but during osteoclast differentiation, Eos association with Ctsk and Acp5 promoters was significantly decreased. Subsequently, MITF and PU.1 recruited coactivators to these target genes, resulting in robust expression of target genes. Overexpression of Eos in bone marrow-derived precursors disrupted osteoclast differentiation and selectively repressed transcription of MITF/PU.1 targets, while small interfering RNA knockdown of Eos resulted in increased basal expression of Ctsk and Acp5. This work provides a mechanism to account for the modulation of MITF and PU.1 activity in committed myeloid progenitors prior to the initiation of osteoclast differentiation in response to the appropriate extracellular signals.