The 'de novo' DNA methyltransferase Dnmt3b compensates the Dnmt1-deficient intestinal epithelium.
The 'de novo' DNA methyltransferase Dnmt3b compensates the Dnmt1-deficient intestinal epithelium.
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DOI：
10.7554/elife.12975
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发表时间：
2016-01-25
期刊：
影响因子：
7.7
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Elliott EN;Sheaffer KL;Kaestner KH
Dnmt 1对出生后的肠道发育至关重要，但不是成年肠上皮细胞生存所必需的，成年肠上皮细胞是唯一快速分裂的体细胞组织。急性Dnmt 1缺失导致显著的低甲基化和基因组不稳定性。DNA甲基化状态和肠道健康的恢复依赖于从头甲基转移酶Dnmt 3b。在肠上皮中消融Dnmt 1和Dnmt 3b是致命的，而缺失Dnmt 1或Dnmt 3b对存活没有影响。这些结果表明，Dnmt 1和Dnmt 3b合作，以维持DNA甲基化和基因组的完整性在肠上皮细胞。DOI：http://dx.doi.org/10.7554/eLife.12975.001细胞中的基因可以根据细胞的需要在不同的时间打开或关闭。小的化学基团可以附着在基因的DNA上，这决定了它是激活还是失活。例如，甲基可以通过称为DNA甲基转移酶的酶连接到DNA上，这一过程称为DNA甲基化。在哺乳动物中，DNA甲基化的模式随着胚胎发育而以高度调节的方式变化。缺乏DNA甲基转移酶1或DNA甲基转移酶3b（简称Dnmt 1或Dnmt 3b）的小鼠在出生前死亡。人们还普遍认为，Dnmt 1是需要在分裂细胞中保持DNA甲基化模式，这种酶通常被称为“维持”甲基转移酶，因为它在新形成的细胞中维持DNA甲基化模式。形成动物肠道的上皮细胞不断地从被称为隐窝的肠道褶皱中发现的分裂细胞产生。这些细胞是动物中分裂最快的细胞之一，在整个成年期每三到五天更换一次。最近在2015年，研究人员删除了成年小鼠肠道细胞中的Dnmt 1基因。这导致DNA甲基化减少并导致异常基因激活。然而，隐窝细胞仍然能够形成新的细胞来更新肠道。Elliott，Sheaffer和Kaestner -他们都参与了之前的研究-现在已经探索了为什么成年小鼠的肠道细胞可以在没有Dnmt 1的情况下存活。首先，实验表明，突变小鼠在基因缺失后两个月内恢复了正常水平的DNA甲基化。进一步的分析发现，这种恢复是由于Dnmt 3b在缺乏Dnmt 1的细胞中被激活，然后重新甲基化DNA。删除Dnmt 1和Dnmt 3b基因导致DNA甲基化丧失，许多成年小鼠过早死亡。以前，人们认为Dnmt 3b只起建立新的DNA甲基化模式的作用，但这些最新的发现表明，这种酶也可以起“维持”甲基转移酶的作用。这些发现还表明，Dnmt 1和Dnmt 3b合作维持成年小鼠肠道上皮细胞的甲基化。下一步的工作可能会调查身体其他组织是否也是如此。DOI：http://dx.doi.org/10.7554/eLife.12975.002网站
Dnmt1 is critical for immediate postnatal intestinal development, but is not required for the survival of the adult intestinal epithelium, the only rapidly dividing somatic tissue for which this has been shown. Acute Dnmt1 deletion elicits dramatic hypomethylation and genomic instability. Recovery of DNA methylation state and intestinal health is dependent on the de novo methyltransferase Dnmt3b. Ablation of both Dnmt1 and Dnmt3b in the intestinal epithelium is lethal, while deletion of either Dnmt1 or Dnmt3b has no effect on survival. These results demonstrate that Dnmt1 and Dnmt3b cooperate to maintain DNA methylation and genomic integrity in the intestinal epithelium. DOI: http://dx.doi.org/10.7554/eLife.12975.001 Genes in a cell can be switched on or off at different times depending on the cell’s requirements. Small chemical groups can be attached to the gene’s DNA, which dictates whether it is activated or inactivated. For example, methyl groups can be attached to DNA by enzymes known as DNA methytransferases in a process called DNA methylation. In mammals, the pattern of DNA methylation changes in a highly regulated manner as the embryo develops. Mice that lack enzymes called DNA methytransferase 1 or DNA methytransferase 3b (shortened to Dnmt1 or Dnmt3b) die before they are born. It is also widely believed that Dnmt1 is needed to preserve DNA methylation patterns in dividing cells, and this enzyme is often called a ‘maintenance’ methyltransferase because it maintains the DNA methylation pattern in newly formed cells. Epithelial cells that form an animal’s intestine are constantly being produced from dividing cells found in folds of the intestine called crypts. These cells are among the most rapidly dividing cells in animals, and are replaced every three to five days throughout adult life. Recently in 2015, researchers deleted the gene for Dnmt1 in intestinal cells in adult mice. This caused a reduction in DNA methylation and led to abnormal gene activation. However, the crypt cells were still able to form new cells to renew the intestine. Elliott, Sheaffer and Kaestner – who were all involved in the previous study – have now explored why intestinal cells in adult mice can survive without Dnmt1. First, the experiments showed that the mutant mice recovered their normal levels DNA methylation within two months of the gene deletion. Further analysis uncovered that this recovery was due to the fact that Dnmt3b became activated in Dnmt1-lacking cells, and then re-methylated the DNA. Deleting the genes for both Dnmt1 and Dnmt3b led to loss of DNA methylation and many of the adult mice died prematurely. Previously, it was thought that Dnmt3b only acted to establish new DNA methylation patterns, but these latest findings suggest that this enzyme can act a ‘maintenance’ methyltransferase as well. Together the findings also reveal that Dnmt1 and Dnmt3b cooperate to maintain methylation in the epithelial cells in the intestines of adult mice. Further work could next investigate if this is also the case for other tissues in the body. DOI: http://dx.doi.org/10.7554/eLife.12975.002