Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1
Epigenetic regulation of hematopoietic differentiation by Gfi-1 and Gfi-1b is mediated by the cofactors CoREST and LSD1
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DOI：
10.1016/j.molcel.2007.06.039
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发表时间：
2007-08-17
期刊：
影响因子：
16
通讯作者：
Orkin, Stuart H.
中科院分区：
文献类型：
--
作者：
Saleque, Shireen;Kim, Jonghwan;Orkin, Stuart H.
Gfi-1和Gfi-1裸露的同源转录抑制因子参与不同的发育环境，包括hernatopoiesis和肿瘤发生。Gfi蛋白的转录抑制需要保守的SNAG结构域。为了阐明Gfi蛋白的功能，我们纯化了Gfi-1 B复合物并鉴定了相互作用的蛋白。其中突出的是辅阻遏物CoREST、组蛋白脱甲基酶LSID 1和HDAC 1和2。CoREST和LSD 1通过SNAG抑制结构域与Gfi-1/1 B结合。Gfi-1 B进一步在体内将这些辅因子募集到大多数靶基因启动子。CoREST和LSID 1的抑制扰乱红系细胞、巨核细胞和粒细胞以及初级红系祖细胞的分化。LSD 1缺失以谱系特异性模式解除Gfi靶点的抑制，伴随着在相应启动子处增强的组蛋白3赖氨酸4甲基化。总体而言，我们表明，染色质调节蛋白CoREST和LSD 1介导的Gfi蛋白的转录抑制。这些辅因子的谱系限制性部署;通过与Gfi蛋白的相互作用控制造血分化。
Gfi-1 and Gfi-1 bare homologous transcriptional repressors involved in diverse developmental contexts, including hernatopoiesis and oncogenesis. Transcriptional repression by Gfi proteins requires the conserved SNAG domain. To elucidate the function of Gfi proteins, we purified Gfi-1 b complexes and identified interacting proteins. Prominent among these is the corepressor CoREST, the histone demethylase LSID1, and HDACs 1 and 2. CoREST and LSD1 associate with Gfi-1/1 b via the SNAG repression domain. Gfi-1 b further recruits these cofactors to the majority of target gene promoters in vivo. Inhibition of CoREST and LSID1 perturbs differentiation of erythroid, megakaryocytic, and granulocytic cells as well as primary erythroid progenitors. LSD1 depletion derepresses Gfi targets in lineage-specific patterns, accompanied by enhanced histone 3 lysine 4 methylation at the respective promoters. Overall, we show that chromatin regulatory proteins CoREST and LSD1 mediate transcriptional repression by Gfi proteins. Lineage-restricted deployment of these cofactors; through interaction with Gfi proteins controls hematopoietic differentiation.