Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.
Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency.
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DOI：
10.1038/srep29454
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发表时间：
2016-07-19
影响因子：
4.6
通讯作者：
Honda H
中科院分区：
文献类型：
--
作者：
Ikeda K;Ueda T;Yamasaki N;Nakata Y;Sera Y;Nagamachi A;Miyama T;Kobayashi H;Takubo K;Kanai A;Oda H;Wolff L;Honda Z;Ichinohe T;Matsubara A;Suda T;Inaba T;Honda H
多梳抑制复合物2（PRC 2）通过组蛋白H3 K27的甲基化参与转录抑制。WD-重复蛋白胚胎外胚层发育（EED）是PRC 2的非催化但重要的组成部分，并且在造血系统恶性肿瘤中鉴定出其突变。为了阐明EED在成人造血和白血病发生中的作用，我们产生了Eed条件性敲除（EedΔ/Δ）小鼠。EedΔ/Δ小鼠在短期内死亡，造血细胞迅速减少。造血干/祖细胞（HSPCs）明显减少，骨髓（BM）再生能力受损。HSPCs的细胞周期分析显示S期分数增加，同时G 0/G1期进入受到抑制。编码细胞粘附分子的基因在EedΔ/Δ HSPC中显著富集，并且一致地，EedΔ/Δ HSPC表现出与主要细胞外基质组分纤连蛋白的附着增加。因此，EED缺陷一方面促进细胞增殖，另一方面可能通过增强对造血小生境的粘附促进细胞静止，这些相互矛盾的事件将导致EedΔ/Δ HSPCs的异常分化和功能缺陷。此外，Eed单倍不足可诱导造血发育不良，Eed杂合子小鼠易发生恶性转化，并与Evi 1过表达协同发生白血病。我们的研究结果表明EED在正常造血和白血病发生中具有分化阶段特异性和剂量依赖性作用。
Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (EedΔ/Δ) mice. EedΔ/Δ mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in EedΔ/Δ HSPCs, and consistently, EedΔ/Δ HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of EedΔ/Δ HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis.