Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1

Iwanami, Norimasa; Takeshita, Kohei; Lawir, Divine-Fondzenyuy; Suetake, Isao; Tajima, Shoji; Sikora, Katarzyna; Trancoso, Ines; O'Meara, Connor; Siamishi, Iliana; Takahama, Yousuke; Furutani-Seiki, Makoto; Kondoh, Hisato; Yonezawa, Yasushige; Schorpp, Michael; Boehm, Thomas

doi:10.1016/j.isci.2020.101260

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Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1

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Iwanami, Norimasa
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lawir, Divine-Fondzenyuy
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sikora, Katarzyna
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Trancoso, Ines
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

O'Meara, Connor
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Siamishi, Iliana
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Schorpp, Michael
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Boehm, Thomas
Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.sciencedirect.com/science/article/pii/S2589004220304466?via%3Dihub
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Citation

Iwanami, N., Takeshita, K., Lawir, D.-F., Suetake, I., Tajima, S., Sikora, K., et al. (2020). Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1. iScience, 23: 101260. doi:10.1016/j.isci.2020.101260.

Cite as: https://hdl.handle.net/21.11116/0000-0007-D128-0

Abstract

DNA methylation is a universal epigenetic mechanism involved in regulation of gene expression and genome stability. The DNA maintenance methylase DNMT1 ensures that DNA methylation patterns are faithfully transmitted to daughter cells during cell division. Because loss of DNMT1 is lethal, a pan-organismic analysis of DNMT1 function is lacking. We identified new recessive dnmt1 alleles in medaka and zebrafish and, guided by the structures of mutant proteins, generated a recessive variant of mouse Dnmt1. Each of the three missense mutations studied here distorts the catalytic pocket and reduces enzymatic activity. Because all three DNMT1 mutant animals are viable, it was possible to examine their phenotypes throughout life. The consequences of genome-wide hypomethylation of DNA of somatic tissues in the Dnmt1 mutants are surprisingly mild but consistently affect the development of the lymphoid lineage. Our findings indicate that developing lymphocytes in vertebrates are sensitive to perturbations of DNA maintenance methylation.