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

DNA N6-甲基腺嘌呤的表征及其在表观遗传记忆中的作用

基本信息

批准号：
10001093
负责人：
Eric Lieberman Greer
金额：
$ 0.12万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-08-31
项目状态：
已结题

项目摘要

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.

抽象的最近，非遗传信息已被证明可以调节越来越多的复杂基因。表型，包括外表、能量代谢、行为状态和寿命。如何表观遗传信息是否代代相传仍然很大程度上未知。任何东西都在受精卵不是DNA本身，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 C. elegans，我们已经描述了跨代的几个例子表观遗传，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 6 位 (6mA)，以前被认为只发生在单细胞生物中。我们是第一个发现这一点的人后生动物中的甲基化，还发现这种修饰在以下范式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表征真核生物中这种新颖的表观遗传修饰：确定 6mA 修饰发生在哪些特定组织和基因组位置。我们还将确定并表征添加、去除和识别这种修饰的酶。最后我们将结合代谢甲基标记和定向甲基化和去甲基化以确定 6mA 是否可遗传材料。该应用程序将共同定义保守的表观遗传调控的基本新层和开始确定 6mA 是否可以跨代传递分子记忆。