@article{97e18f59a39e4c5ab791268eacfba1a1,
title = "Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis",
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.",
keywords = "5-hydroxymethylcytosine, 5hmC, CLL, HSCs, MDS, Tet2, chronic lymphocytic leukemia, hematopoietic stem cells, myelodysplastic syndrome",
author = "Kyoko Ito and Joun Lee and Stephanie Chrysanthou and Yilin Zhao and Katherine Josephs and Hiroyo Sato and Julie Teruya-Feldstein and Deyou Zheng and Dawlaty, {Meelad M.} and Keisuke Ito",
note = "Funding Information: We thank the Einstein epigenomics, flow cytometry (NIH grant P30 CA013330), histopathology, and transgenic cores for help with RNA-seq, cell sorting, sectioning tissues, and blastocyst injections, respectively. We are grateful to M. Xu for the Tet2 knockout mouse strain and M. Yoshimoto for the critical discussions of B lymphopoiesis. We thank Q. Tang and other members of the Ito and Dawlaty labs, as well as P.S. Frenette, U. Stiedl, A. Verma, and other members of Einstein Stem Cell Institute, for helpful suggestions and discussions. M.M.D. is supported by the Sidney Kimmel Foundation, the Leukemia Research Foundation, NYSDOH/NYSTEM, and the NIH NIGMS (grant R01GM122839). Keisuke Ito is supported by the NIH NIDDK (grants R01DK98263, R01DK115577, and R01DK100689) and NYSDOH as core director of Einstein single-cell genomics/epigenomics (C029154). M.M.D. and Keisuke Ito are also supported by funds from the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein, as well as by the NIH NHLBI (grant R01HL148852 to M.M.D. and Keisuke Ito as multi-PIs). S.C. is supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund (C30292GG). Y.Z. and D.Z. are in part supported by the NIH NEI (grants R01 EY014237 and EY012200). Keisuke Ito is a Scholar of The Leukemia and Lymphoma Society (#1360-19). Kyoko Ito performed analyses of hematopoietic tissues and their function. J.L. and K.J. established and monitored mouse cohort study and performed necropsy. Kyoko Ito and J.L. carried out histology and J.T.-F. performed pathological analyses. Y.Z. and D.Z. analyzed the RNA-seq and ChIP-seq data. H.S. provided technical support. S.C. supported the molecular analyses. M.M.D. and Keisuke Ito designed the study, supervised execution of experiments, secured funding, and wrote the manuscript with input from other authors. The authors declare no competing interests. Funding Information: We thank the Einstein epigenomics, flow cytometry ( NIH grant P30 CA013330 ), histopathology, and transgenic cores for help with RNA-seq, cell sorting, sectioning tissues, and blastocyst injections, respectively. We are grateful to M. Xu for the Tet2 knockout mouse strain and M. Yoshimoto for the critical discussions of B lymphopoiesis. We thank Q. Tang and other members of the Ito and Dawlaty labs, as well as P.S. Frenette, U. Stiedl, A. Verma, and other members of Einstein Stem Cell Institute, for helpful suggestions and discussions. M.M.D. is supported by the Sidney Kimmel Foundation , the Leukemia Research Foundation , NYSDOH / NYSTEM , and the NIH NIGMS (grant R01GM122839 ). Keisuke Ito is supported by the NIH NIDDK (grants R01DK98263 , R01DK115577 , and R01DK100689 ) and NYSDOH as core director of Einstein single-cell genomics/epigenomics ( C029154 ). M.M.D. and Keisuke Ito are also supported by funds from the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein, as well as by the NIH NHLBI (grant R01HL148852 to M.M.D. and Keisuke Ito as multi-PIs). S.C. is supported by the Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund ( C30292GG ). Y.Z. and D.Z. are in part supported by the NIH NEI (grants R01 EY014237 and EY012200 ). Keisuke Ito is a Scholar of The Leukemia and Lymphoma Society (# 1360-19 ). Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = sep,
day = "3",
doi = "10.1016/j.celrep.2019.07.094",
language = "English (US)",
volume = "28",
pages = "2480--2490.e4",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}
