Dnmt1 expression in pre- and postimplantation embryogenesis and the maintenance of IAP silencing
Dnmt1 expression in pre- and postimplantation embryogenesis and the maintenance of IAP silencing
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DOI：
10.1128/mcb.24.4.1640-1648.2004
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发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
--
作者：
Gaudet, F;Rideout, WM;Jaenisch, R
在小鼠胚胎发育过程中，脑池内A型粒子(IAP)序列的甲基化维持不变。甲基化抑制IAP的表达和通过逆转录转座发生突变的可能性，但尚不清楚在胚胎阶段，当大部分基因组被去甲基化时，这些元件的甲基化是如何维持的。有人认为，在卵裂过程中存在高水平的DNA甲基转移酶-1(DNMT1)，这可能是保持IAP甲基化的重要因素。为了验证这一假设，我们将Dnmt1的突变等位基因与刺鼠等位基因(A(Iapy))相结合，这为刺鼠My插入的甲基化状态提供了毛色读数。我们发现，Dnmt1水平的降低直接影响该基因的甲基化，导致成人刺鼠基因稳定的转录激活。具体地说，母系短的Dnmt1蛋白在卵裂胚胎中维持A(Iapy)基因的甲基化是重要的，而在体细胞中发现的较长的Dnmt1异构体对于在移植后阶段维持IAP甲基化是重要的。这些结果强调了在妊娠期间保持适当甲基化模式的重要性，并表明干扰这一过程可能稳定地影响成人的基因表达模式，并可能产生深远的表型后果。
The methyllation of intracisternal A-type particle (IAP) sequences is maintained during mouse embryogenesis. Methylation suppresses IAP expression and the potential for mutagenesis by retrotransposition, but it is not clear how methylation of these elements is maintained during the embryonic stages when the bulk of the genome is being demethylated. It has been suggested that the high levels of DNA methyltransferase-1 (Dnmt1) present during cleavage could be important for keeping IAPs methylated. To test this hypothesis, we combined mutant alleles of Dnmt1 with an agouti allele (A(iapy)), which provided a coat color readout for the methylation status of the MY insertion in the agouti locus. We found that reduction in Dnmt1 levels directly impacted methylation at this locus, leading to stable transcriptional activation of the agouti gene in the adult. Specifically, the short maternal Dnmt1 protein was important in maintaining methylation at the A(iapy) locus in cleavage embryos, whereas the longer Dnmt1 isoform, found in somatic cells was important in maintaining IAP methylation during the postimplantation stage. These results underscore the importance of maintaining proper maintenance of methylation patterns during gestation and suggest that interference with this process may stably affect gene expression patterns in the adult and may have profound phenotypic consequences.