Induction of tumors in mice by genomic hypomethylation
Induction of tumors in mice by genomic hypomethylation
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DOI：
10.1126/science.1083558
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发表时间：
2003-04-18
期刊：
影响因子：
56.9
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
--
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
许多人类癌症中都发生全基因组 DNA 低甲基化，但这种表观遗传变化是肿瘤发生的原因还是结果尚不清楚。为了探索这一现象，我们培育了携带低效 DNA 甲基转移酶 1 (Dnmt1) 等位基因的小鼠，该等位基因将 Dnmt1 表达降低至野生型水平的 10%，并导致所有组织中显着的全基因组低甲基化。这些突变小鼠在出生时就处于矮小状态，在 4 至 8 个月大时，它们出现了侵袭性 T 细胞淋巴瘤，显示出高频率的 15 号染色体三体性。这些结果表明 DNA 低甲基化可能通过促进染色体不稳定而在肿瘤形成中发挥因果作用。
Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele, which reduces Dnmt1 expression to 10% of wild-type levels and results in substantial genome-wide hypomethylation in all tissues. The mutant mice were runted at birth, and at 4 to 8 months of age they developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability.