Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1

Overview

Journal iScience

Publisher Cell Press

Date 2020 Jun 26

PMID 32585597

Citations 5

Authors

Norimasa Iwanami

Kohei Takeshita

Divine-Fondzenyuy Lawir

Isao Suetake

Shoji Tajima

Katarzyna Sikora

Ines Trancoso

Connor OMeara

Iliana Siamishi

Yousuke Takahama

Makoto Furutani-Seiki

Hisato Kondoh

Yasushige Yonezawa

Michael Schorpp

Thomas Boehm

Affiliations

Soon will be listed here.

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.

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