Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis

Kyoko Ito, Joun Lee, Stephanie Chrysanthou, Yilin Zhao, Katherine Josephs, Hiroyo Sato, Julie Teruya-Feldstein, Deyou Zheng, Meelad M. Dawlaty, Keisuke Ito

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2480-2490.e4
JournalCell Reports
Volume28
Issue number10
DOIs
StatePublished - Sep 3 2019

Fingerprint

Hematopoietic Stem Cells
Gene expression
Homeostasis
DNA
Chromatin
Bone
Animals
Cells
Knockout Mice
Enzymes
Myelodysplastic Syndromes
Hematopoiesis
Transcriptome
Bone Marrow Cells
Down-Regulation
Phenotype
Gene Expression
Neoplasms

Keywords

  • 5-hydroxymethylcytosine
  • 5hmC
  • chronic lymphocytic leukemia
  • CLL
  • hematopoietic stem cells
  • HSCs
  • MDS
  • myelodysplastic syndrome
  • Tet2

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis. / Ito, Kyoko; Lee, Joun; Chrysanthou, Stephanie; Zhao, Yilin; Josephs, Katherine; Sato, Hiroyo; Teruya-Feldstein, Julie; Zheng, Deyou; Dawlaty, Meelad M.; Ito, Keisuke.

In: Cell Reports, Vol. 28, No. 10, 03.09.2019, p. 2480-2490.e4.

Research output: Contribution to journalArticle

Ito, K, Lee, J, Chrysanthou, S, Zhao, Y, Josephs, K, Sato, H, Teruya-Feldstein, J, Zheng, D, Dawlaty, MM & Ito, K 2019, 'Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis', Cell Reports, vol. 28, no. 10, pp. 2480-2490.e4. https://doi.org/10.1016/j.celrep.2019.07.094
Ito, Kyoko ; Lee, Joun ; Chrysanthou, Stephanie ; Zhao, Yilin ; Josephs, Katherine ; Sato, Hiroyo ; Teruya-Feldstein, Julie ; Zheng, Deyou ; Dawlaty, Meelad M. ; Ito, Keisuke. / Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis. In: Cell Reports. 2019 ; Vol. 28, No. 10. pp. 2480-2490.e4.
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