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

摘要 非遗传信息最近被证明可以调节越来越多的复杂的 表型，包括身体外观，能量代谢，行为状态和寿命。如何 表观遗传信息是如何代代相传的，这在很大程度上仍然是未知的。上任何东西 受精卵，不是DNA本身，可以携带这种非遗传信息。在这里我们建议 优势线虫C.在那里，我们描述了几个跨世代的例子， 表观遗传，以确定调节表观遗传记忆的遗传物质。我们已经确定 梭线虫含有一种古老的DNA甲基化形式，位于腺嘌呤嘌呤环的第6位 (6mA)，这在以前被认为只发生在单细胞生物中。我们是第一个发现这个的 甲基化，并发现这种修饰在后生动物的范例中逐渐增加， 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这种新的表观遗传修饰： 识别哪些特定组织和基因组位置发生6 mA修饰。我们还将确定和 表征添加、去除和识别这种修饰的酶。最后我们将联合收割机 甲基标记和定向甲基化和去甲基化，以确定6mA是否是可遗传的 材料总之，这一应用将定义一个基本的新层保守的表观遗传调控， 开始，以确定是否6毫安可以跨代传输分子记忆。

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.