Characterization of DNA N6-methyl adenine and its role in epigenetic memory

摘要 最近研究表明，非遗传信息可以调节越来越多的复合体 表型，包括身体外观、能量代谢、行为状态和寿命。多么 表观遗传信息在一代又一代之间的传播在很大程度上仍然未知。里面的任何东西 受精卵本身并不是DNA，它可以携带这种非遗传信息。在这里，我们建议采取 线虫的优势，我们已经描述了几个跨代线虫的例子 表观遗传，识别调节表观遗传记忆的可遗传物质。我们已经确定了 线虫含有一种古老形式的DNA甲基化，位于腺嘌呤中嘌呤环的第六位 (6 MA)，以前认为只发生在单细胞生物体中。我们是第一个发现这一点的 在后生动物中的甲基化，还发现这种修饰在一个范例中逐渐增加 表观遗传记忆。在这里，我们建议通过以下方式来描述真核生物中的这种新的表观遗传修饰 确定发生6 mA修饰的特定组织和基因组位置。我们还将确定和 描述添加、移除和识别这种修饰的酶的特性。最后，我们将结合新陈代谢 甲基标记和定向甲基化和去甲基化以确定6 mA是否为可遗传的 材料。这一应用将共同定义保守的表观遗传调控的基本新层 开始确定6 mA是否可以跨代传递分子记忆。

Abstract Non-genetic information has recently been shown to regulate an increasing number of complex phenotypes, including physical appearance, energy metabolism, behavioral state, and longevity. How epigenetic information is transmitted from generation to generation is still largely unknown. Anything in the zygote, which is not the DNA itself, could carry this non-genetic information. Here we propose taking advantage of the nematode C. elegans, where we have characterized several examples of transgenerational epigenetic inheritance, to identify the heritable material that regulates epigenetic memory. We have identified that C. elegans contain an ancient form of DNA methylation, on the 6th position of the purine ring in adenines (6mA), which was previously thought to only occur in unicellular organisms. We were the first to identify this methylation in Metazoa and additionally found that this modification increases progressively in a paradigm of epigenetic memory. Here we propose to characterize this novel epigenetic modification in eukaryotes by identifying in which specific tissues and genomic locations 6mA modifications occur. We will also identify and characterize the enzymes that add, remove and recognize this modification. Finally we will combine metabolic methyl-labeling and directed methylation and demethylation to determine whether 6mA is the heritable material. Together this application will define a fundamental new layer of conserved epigenetic regulation and begin to identify whether 6mA can transmit a molecular memory across generations.