Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA; Department of Medicine (Hemato-Oncology), Montefiore Medical Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA.
Cell Rep. 2019 Sep 3;28(10):2480-2490.e4. doi: 10.1016/j.celrep.2019.07.094.
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.
十 - 十一易位（TET）酶通过促进 DNA 去甲基化并与染色质修饰剂合作来调节基因表达。TET2 是该家族的成员，在血液系统疾病中经常发生突变。TET2 在造血中的作用归因于其 DNA 去甲基酶活性，但其非酶活性的意义尚未确定。为了剖析 Tet2 的催化和非催化要求，我们构建了催化失活的 Tet2 突变小鼠，并对 Tet2 突变和 Tet2 敲除动物进行了比较分析。Tet2 敲除小鼠表现出造血干细胞和祖细胞（HSPC）的扩增，并发展出髓系和淋巴系疾病，而 Tet2 突变小鼠主要发展出类似于人类骨髓增生异常综合征的髓系恶性肿瘤。Tet2 敲除小鼠的 HSPC 表现出独特的基因表达谱，包括 Gata2 的下调。在 Tet2 敲除骨髓细胞中过表达 Gata2 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。
