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

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 deme...

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Autores principales: Ito, Kyoko, Lee, Joun, Chrysanthou, Stephanie, Zhao, Yilin, Josephs, Katherine, Sato, Hiroyo, Teruya-Feldstein, Julie, Zheng, Deyou, Dawlaty, Meelad M., Ito, Keisuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750732/
https://www.ncbi.nlm.nih.gov/pubmed/31484061
http://dx.doi.org/10.1016/j.celrep.2019.07.094
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author Ito, Kyoko
Lee, Joun
Chrysanthou, Stephanie
Zhao, Yilin
Josephs, Katherine
Sato, Hiroyo
Teruya-Feldstein, Julie
Zheng, Deyou
Dawlaty, Meelad M.
Ito, Keisuke
author_facet Ito, Kyoko
Lee, Joun
Chrysanthou, Stephanie
Zhao, Yilin
Josephs, Katherine
Sato, Hiroyo
Teruya-Feldstein, Julie
Zheng, Deyou
Dawlaty, Meelad M.
Ito, Keisuke
author_sort Ito, Kyoko
collection PubMed
description 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.
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spelling pubmed-67507322019-09-18 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 Cell Rep Article 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. 2019-09-03 /pmc/articles/PMC6750732/ /pubmed/31484061 http://dx.doi.org/10.1016/j.celrep.2019.07.094 Text en This is an open access article under the CC BY-Nc-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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
title Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
title_full Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
title_fullStr Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
title_full_unstemmed Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
title_short Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis
title_sort non-catalytic roles of tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750732/
https://www.ncbi.nlm.nih.gov/pubmed/31484061
http://dx.doi.org/10.1016/j.celrep.2019.07.094
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