The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation
The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation
复制标题
DOI：
10.1038/sj.emboj.7601824
复制
发表时间：
2007-09-19
期刊：
影响因子：
11.4
通讯作者：
Jain, Mukesh K.
中科院分区：
文献类型：
--
作者：
Feinberg, Mark W.;Wara, Akm Khyrul;Jain, Mukesh K.
单核细胞分化涉及谱系年龄限制性转录因子的参与，尽管这一过程发生的机制还不完全确定。在造血系统中，Kruppel样因子家族（KLF）的成员在红细胞和T淋巴细胞发育中发挥重要作用。我们发现KLF 4/ GKLF在骨髓生成过程中以单核细胞限制性和阶段特异性的模式表达，并具有促进单核细胞分化的功能。KLF 4在HL- 60细胞中的过表达赋予成熟单核细胞的特征。相反，KLF 4敲低阻断佛波酯诱导的单核细胞分化。在克隆形成试验中，原代普通髓系祖细胞（CMPs）或造血干细胞（HSCs）中强制表达KLF 4可诱导单核细胞分化，而KLF 4缺乏可抑制单核细胞但增加粒细胞分化。机制研究表明，KLF 4是PU.1的靶基因。因此，KLF 4可以沿着单核细胞谱系拯救PU. 1-/-胎肝细胞，并且可以激活单核细胞特异性CD 14启动子。因此，KLF 4是控制单核细胞分化的转录网络中的关键调节因子。
Monocyte differentiation involves the participation of line-age-restricted transcription factors, although the mechanisms by which this process occurs are incompletely defined. Within the hematopoietic system, members of the Kruppel-like family of factors ( KLFs) play essential roles in erythrocyte and T lymphocyte development. Here we show that KLF4/ GKLF is expressed in a monocyte- restricted and stage- specific pattern during myelopoiesis and functions to promote monocyte differentiation. Overexpression of KLF4 in HL- 60 cells confers the characteristics of mature monocytes. Conversely, KLF4 knockdown blocked phorbol ester- induced monocyte differentiation. Forced expression of KLF4 in primary common myeloid progenitors ( CMPs) or hematopoietic stem cells ( HSCs) induced exclusive monocyte differentiation in clonogenic assays, whereas KLF4 deficiency inhibited monocyte but increased granulocyte differentiation. Mechanistic studies demonstrate that KLF4 is a target gene of PU.1. Consistently, KLF4 can rescue PU.1-/- fetal liver cells along the monocytic lineage and can activate the monocytic- specific CD14 promoter. Thus, KLF4 is a critical regulator in the transcriptional network controlling monocyte differentiation.