Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1
Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1
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DOI：
10.1016/j.isci.2020.101260
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发表时间：
2020-07-24
期刊：
影响因子：
5.8
通讯作者：
Boehm, Thomas
中科院分区：
文献类型：
--
作者：
Iwanami, Norimasa;Takeshita, Kohei;Boehm, Thomas
DNA甲基化是一种普遍的表观遗传学机制，参与基因表达和基因组稳定性的调控。DNA维持甲基化酶DNMT1确保DNA甲基化模式在细胞分裂期间忠实地传递给子细胞。由于DNMT1的缺失是致命的，因此缺乏对DNMT1功能的泛器官分析。我们在青鳉和斑马鱼中发现了新的隐性dnmt 1等位基因，并在突变蛋白结构的指导下，产生了小鼠dnmt 1的隐性变体。这里研究的三个错义突变中的每一个都会扭曲催化口袋并降低酶活性。由于所有三种DNMT1突变动物都是可行的，因此可以在整个生命过程中检查它们的表型。Dnmt 1突变体中体细胞组织DNA全基因组低甲基化的后果令人惊讶地温和，但始终影响淋巴谱系的发育。我们的研究结果表明，在脊椎动物的发展淋巴细胞是敏感的DNA维持甲基化的扰动。
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.