文章基本信息

标题：Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1
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作者：Norimasa Iwanami ; Kohei Takeshita ; Divine-Fondzenyuy Lawir 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：7
页码：1-38
DOI：10.1016/j.isci.2020.101260
语种：English
出版社：Elsevier
摘要：SummaryDNA 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 recessivednmt1alleles in medaka and zebrafish and, guided by the structures of mutant proteins, generated a recessive variant of mouseDnmt1. 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 theDnmt1mutants 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.Graphical AbstractDisplay OmittedHighlights•Genetic screens identified recessive viable missense alleles ofdnmt1in teleosts•A viable mouse Dnmt1 mutant generated by structure-guided precision mutagenesis•Missense mutations distort the catalytic pocket and reduce enzymatic activity•DNA hypomethylation consistently affects development of the lymphoid lineageMolecular Genetics; Phenotyping; Transcriptomics