Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice.
Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice.
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在小鼠表观遗传敏感等位基因上DNA甲基化的动态重编程。
DOI：
10.1371/journal.pgen.0020049
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发表时间：
2006-04
期刊：
影响因子：
4.5
通讯作者：
Whitelaw E
中科院分区：
文献类型：
--
作者：
Blewitt ME;Vickaryous NK;Paldi A;Koseki H;Whitelaw E
越来越多的证据表明，在植物和动物中，表观遗传标记并不总是在世代之间被清除。与可测量的表型相关的基因的不完全擦除导致从一代到下一代的不寻常的遗传模式，称为跨代表观遗传。Agglutinase viable yellow（Avy）等位基因是在小鼠中研究这种现象的最好例子。Avy等位基因是Agglutinase基因上游的反转录转座子插入的结果。该基因座的表达受逆转录转座子的长末端重复序列（LTR）控制，表达导致黄色外壳，并与LTR的低甲基化相关。同基因小鼠表现出不同的表现力，导致小鼠具有一系列毛色，从黄色到棕色。Agglutination小鼠具有甲基化的LTR。该基因座显示表观遗传遗传后，母亲，但不是父亲的传输;黄色的母亲产生更多的黄色后代比agrabitant母亲。我们分析了成熟配子、合子和囊胚中的DNA甲基化，发现父系和母系遗传的等位基因被不同地对待。父系遗传的等位基因会迅速去甲基化，而母系等位基因的去甲基化速度较慢，其方式类似于非印记单拷贝基因。有趣的是，在该等位基因的母体传递后，胚泡中没有DNA甲基化，这表明DNA甲基化不是遗传标记。我们从不涉及DNA甲基化直接分析的研究中独立支持这一结论。多梳组蛋白Mel 18的单倍不足在父系来源的Avy等位基因处引入表观遗传，并且系谱揭示这发生在合子基因组激活之后，因此，尽管该位点快速去甲基化。现在，从人类流行病学研究和动物和植物遗传学研究中，有相当数量的证据表明，除了初级DNA序列之外，其他信息也会代代相传，并会影响后代的表型。研究人员将这些信息称为表观遗传，并且人们对发现这种表观遗传信息的分子基础很感兴趣。他们现在知道了很多关于各种类型的表观遗传标记的信息，这些标记在生物体的生命中调节基因组的表达，这些标记包括对DNA分子本身的修饰，特别是DNA甲基化和对将DNA包装到染色体中的蛋白质的修饰，称为染色质。DNA甲基化似乎是最稳定的表观遗传修饰之一，并且是负责跨代表观遗传的分子的主要候选者。这里呈现的结果表明，DNA甲基化不是遗传的表观遗传标记，至少在本研究中使用的小鼠模型中是这样。
There is increasing evidence in both plants and animals that epigenetic marks are not always cleared between generations. Incomplete erasure at genes associated with a measurable phenotype results in unusual patterns of inheritance from one generation to the next, termed transgenerational epigenetic inheritance. The Agouti viable yellow (Avy) allele is the best-studied example of this phenomenon in mice. The Avy allele is the result of a retrotransposon insertion upstream of the Agouti gene. Expression at this locus is controlled by the long terminal repeat (LTR) of the retrotransposon, and expression results in a yellow coat and correlates with hypomethylation of the LTR. Isogenic mice display variable expressivity, resulting in mice with a range of coat colours, from yellow through to agouti. Agouti mice have a methylated LTR. The locus displays epigenetic inheritance following maternal but not paternal transmission; yellow mothers produce more yellow offspring than agouti mothers. We have analysed the DNA methylation in mature gametes, zygotes, and blastocysts and found that the paternally and maternally inherited alleles are treated differently. The paternally inherited allele is demethylated rapidly, and the maternal allele is demethylated more slowly, in a manner similar to that of nonimprinted single-copy genes. Interestingly, following maternal transmission of the allele, there is no DNA methylation in the blastocyst, suggesting that DNA methylation is not the inherited mark. We have independent support for this conclusion from studies that do not involve direct analysis of DNA methylation. Haplo-insufficiency for Mel18, a polycomb group protein, introduces epigenetic inheritance at a paternally derived Avy allele, and the pedigrees reveal that this occurs after zygotic genome activation and, therefore, despite the rapid demethylation of the locus. There is now a reasonable amount of evidence from both epidemiological studies in humans and from genetic studies in animals and plants that information in addition to the primary DNA sequence is inherited across generations and can influence the phenotype of the offspring. Researchers refer to this information as epigenetic, and there is much interest in discovering the molecular basis for this epigenetic information. They now know a great deal about the various types of epigenetic marks that regulate the expression of the genome within the life of an organism, and these include both modifications to the DNA molecule itself, specifically DNA methylation and modifications to the proteins that package the DNA into chromosomes, termed chromatin. DNA methylation appears to be one of the most stable epigenetic modifications and has been the primary candidate for the molecule responsible for transgenerational epigenetic inheritance. The results presented here suggest that DNA methylation is not the inherited epigenetic mark, at least in the mouse model used in this study.
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