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：
9165246
负责人：
Eric Lieberman Greer
金额：
$ 265.5万
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.

抽象的最近已显示非遗传信息可以调节越来越多的复合物表型，包括外观，能量代谢，行为状态和寿命。如何表观遗传信息是世代传播的，仍然在很大程度上未知。任何东西合子本身不是DNA本身，可以携带这种非遗传信息。在这里我们提出服用线虫C.秀隐岩的优势，我们在其中表征了几个跨代示例表观遗传遗传，以确定调节表观遗传记忆的可遗传材料。我们已经确定了秀丽隐杆线虫含有一种古老的DNA甲基化，在嘌呤环在腺丝中的第6个位置（6MA），以前被认为仅发生在单细胞生物中。我们是第一个识别这一点的人后生动物中的甲基化，此外发现这种修饰在范式中逐渐增加表观遗传记忆。在这里，我们建议通过通过真核生物中这种新颖的表观遗传修饰来表征确定在哪些特定组织和基因组位置发生6MA修饰。我们还将确定和表征添加，删除和识别此修饰的酶。最后我们将结合代谢甲基标记和定向甲基化和脱甲基化，以确定6ma是否是可遗传的材料。该应用程序将共同定义一个基本的保守表观遗传调节的新层和开始确定6MA是否可以在世代上传输分子记忆。