Forced expression of the histone demethylase Fbxl10 maintains, self-renewing hematopoietic stem cells
Forced expression of the histone demethylase Fbxl10 maintains, self-renewing hematopoietic stem cells
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DOI：
10.1016/j.exphem.2011.03.008
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发表时间：
2011-06-01
影响因子：
2.6
通讯作者：
Iwama, Atsushi
中科院分区：
文献类型：
--
作者：
Konuma, Takaaki;Nakamura, Shunsuke;Iwama, Atsushi
Objective.组蛋白的甲基化状态根据细胞环境发生显著变化，并定义了细胞类型特异性基因表达谱。组蛋白去甲基化酶最近被牵连在这个过程中。然而，它是未知的组蛋白去甲基化酶如何在自我更新造血干细胞（HSC）的维护功能。材料和方法。我们分析了组蛋白去甲基化酶基因在小鼠造血细胞中的表达，并列出了在HSC中优先表达的基因。我们通过使用逆转录病毒系统转导CD 34（-）c-Kit（+）Sca-1（+）谱系标志物（CD 34（-）KSL）HSC，随后进行体外甲基纤维素集落测定和体内竞争性再增殖测定，分析了所选基因的影响。结果我们发现F-box和富含亮氨酸的重复蛋白10（Fbxl 10，也称为Jhdm 1b或Kdm 2b）在CD 34（-）KSL HSC中高度表达。Fbxl 10编码对组蛋白H3在赖氨酸36处单/二甲基化（H3 K36 me 1/me 2）具有特异性的脱甲基酶，并与多梳组蛋白（HSC的基本调节剂）形成复合物。Fbxl 10在HSC中的强制表达扩大了培养物中具有多系分化潜力的集落形成细胞的数量，并防止了连续移植后HSC的长期再增殖潜力的耗尽。Fbxl 10通过直接结合其启动子和基因体以及H3 K36的去甲基化，紧密抑制细胞周期蛋白依赖性激酶抑制剂基因（包括Ink 4a、Ink 4 b和Ink 4c）的表达。H2 A在靶位点的单泛素化水平的增加也表明Fbxl 10与多梳组蛋白的协作。结论.我们的研究结果暗示Fbxl 10在维持造血干细胞的自我更新能力，从而突出了第一次在造血干细胞的表观遗传调控组蛋白去甲基化的作用。(C)2011 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Objective. The methylation status of histones changes dramatically depending on cellular context and defines cell type-specific gene expression profiles. Histone demethylases have recently been implicated in this process. However, it is unknown how histone demethylases function in the maintenance of self-renewing hematopoietic stem cells (HSCs). Materials and Methods. We profiled the expression of histone demethylase genes in mouse hematopoietic cells and listed genes preferentially expressed in HSCs. We analyzed the impact of a selected gene by transducing CD34(-) c-Kit(+)Sca-1(+)lineage marker (CD34(-)KSL) HSCs using retroviral system followed by in vitro methylcellulose colony assays and in vivo competitive repopulation assays. Results. We found that F-box and leucine-rich repeat protein 10 (Fbxl10, also known as Jhdm1b or Kdm2b), is highly expressed in CD34(-)KSL HSCs. Fbxl10 encodes a demethylase specific to the histone H3 mono/di-methylated at lysine 36 (H3K36me1/me2) and forms complexes with polycomb-group proteins, essential regulators of HSCs. Forced expression of Fbxl10 in HSCs expanded numbers of colony-forming cells with multilineage differentiation potential in culture and prevented exhaustion of the long-term repopulating potential of HSCs following serial transplantation. Fbxl10 tightly repressed the expression of cyclin-dependent kinase inhibitor genes, including Ink4a, Ink4b, and Ink4c, through direct binding to their promoters and gene bodies and demethylation at H3K36. Increased levels of monoubiquitylation of H2A at target loci also suggested the collaboration of Fbxl10 with polycomb-group proteins. Conclusions. Our findings implicate Fbxl10 in the maintenance of self-renewal capacity of HSCs, thus highlight a role of histone demethylation for the first time in the epigenetic regulation of HSCs. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.