Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
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DOI：
10.1016/j.celrep.2019.07.094
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发表时间：
2019-09-03
期刊：
影响因子：
8.8
通讯作者：
Ito, Keisuke
中科院分区：
文献类型：
--
作者：
Ito, Kyoko;Lee, Joun;Ito, Keisuke
10-11 易位 (TET) 酶通过促进 DNA 去甲基化并与染色质修饰剂配合来调节基因表达。 TET2 是该家族的成员，在血液疾病中经常发生突变。 TET2 在造血过程中的贡献归因于其 DNA 去甲基化酶活性，其非酶功能的重要性仍不清楚。为了剖析 Tet2 的催化和非催化需求，我们设计了催化失活的 Tet2 突变小鼠，并对 Tet2 突变体和 Tet2 敲除动物进行了比较分析。 Tet2基因敲除小鼠表现出造血干细胞和祖细胞（HSPC）的扩增，并出现骨髓和淋巴系统疾病，而Tet2突变小鼠主要出现骨髓恶性肿瘤，让人想起人类骨髓增生异常综合征。 Tet2 敲除小鼠的 HSPC 表现出独特的基因表达谱，包括 Gata2 的下调。 Tet2 敲除骨髓细胞中 Gata2 的过度表达可改善疾病表型。我们的结果揭示了 TET2 在 HSPC 稳态中的非催化作用。
The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis.