Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1

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

doi:10.1016/j.isci.2020.101260

Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1

iScience. 2020 Jul 24;23(7):101260. doi: 10.1016/j.isci.2020.101260. Epub 2020 Jun 10.

Authors

Affiliations

¹ Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. Electronic address: iwanami@cc.utsunomiya-u.ac.jp.
² RIKEN SPring-8 Center, Sayo, Hyogo 679-5148, Japan.
³ Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany.
⁴ Laboratory of Epigenetics, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan.
⁵ Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Division of Experimental Immunology, Institute of Advanced Medical Sciences, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
⁶ Systems Biochemistry in Pathology and Regeneration, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
⁷ Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan.
⁸ High Pressure Protein Research Center, Institute of Advanced Technology, Kindai University, 930 Nishimitani, Kinokawa, Wakayama 649-6493, Japan.
⁹ Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, 79108 Freiburg, Germany. Electronic address: boehm@ie-freiburg.mpg.de.

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.

Keywords: Molecular Genetics; Phenotyping; Transcriptomics.