Identification and characterization of methyl-deoxyadenosine in the eukaryotic genome.

真核基因组中甲基脱氧腺苷的鉴定和表征。

• 批准号: BB/M022994/1
• 负责人: John Gurdon
• 金额: $ 105.83万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM022994%2F1
• 关键词: Identification; characterization; methyl; deoxyadenosine; eukaryotic

The aim of our proposal is to study a novel, currently unreported modification that can directly modify a part of the genetic material, and to determine how this affects an organism. DNA encodes the genetic instructions used in the development and functioning of all living organisms. It is composed of 4 molecules. About 30 years ago, it was discovered that one of these DNA molecules could be directly modified on a molecular level. This modification, occurring on the molecule called dC, has been studied extensively ever since, revealing a fundamental role in different biological pathways and a better understanding of many human diseases such as cancer. Ultimately, research in this field has led to new drug therapies and improved human health.Since the discovery that dC can be modified, no other DNA molecule has been known to undergo direct molecular alterations. However, just recently we have discovered the presence of a modification on another DNA molecule, namely affecting the DNA molecule dA. This novel finding has so far not been reported and is still unknown to the research community. Hence, the aim of our proposal is to study this novel and direct DNA modification and determine how it affects an organism. Since this novel modification directly alters the DNA, the building blocks of 'life', it has the potential to generate a similar fundamental impact on biology and human health as the discovery of the modification affecting dC had and still continues to do. Hence, we would like to investigate this novel modification. Every cell of an organism has the same DNA. However, molecular modifications ensure that even though the DNA is the same in every cell type, the cells still differ. For example, a liver cell is different and has other functions from a skin cell. We have recently established that the dA modification varies between different cell types. This suggests that this novel modification could be responsible for the differences observed between different cell types. To get a better understanding of the novel dA modification, we will describe and compare the location of the dA modification in different cell types. By studying this modification during the early development of an organism, we will get a better understanding how this novel modification is established and regulated on a molecular level. Due to ethical concerns, experiments on human development cannot be performed. However, to understand the underlying molecular events, researchers use animal model organisms that have similar and conserved molecular mechanisms. In our case, we use the frog, which is a commonly used model organism to study the development of an organism and the differences between different cell types.Ultimately, we expect that our research will lead to the better understanding why different cell types are distinct despite having the same genetic instruction. In future, this information could be used for medical purposes and the generation of organs for tissue replacement therapies. Bearing in mind that any errors in the modification affecting dC can lead to various diseases such as cancer, it is likely that the misregulations of the novel modification dA could also cause health defects. Hence, it is vital to study this novel dA modification, as this has the potential to open up the knowledge of currently unknown causes of disease. This knowledge is essential to path the way for novel and better future drug therapies, ultimately benefiting human health.

我们提案的目的是研究一种新颖的、目前尚未报道的修饰，它可以直接修改部分遗传物质，并确定这如何影响生物体。DNA对所有生物的发育和功能所使用的遗传指令进行编码。它由4个分子组成。大约30年前，人们发现其中一种DNA分子可以在分子水平上进行直接修饰。这种修饰发生在名为DC的分子上，自那以后一直被广泛研究，揭示了在不同生物途径中的基础作用，并更好地理解了许多人类疾病，如癌症。最终，这一领域的研究带来了新的药物疗法并改善了人类健康。自从发现DC可以被修饰以来，还没有其他DNA分子发生直接的分子改变。然而，就在最近，我们发现了另一种DNA分子的修饰，即影响DNA分子da。这一新发现到目前为止还没有报道，研究界仍然不知道。因此，我们建议的目的是研究这种新颖和直接的DNA修饰，并确定它如何影响生物体。由于这种新的修饰直接改变了DNA，这是“生命”的基石，它有可能对生物学和人类健康产生类似的根本性影响，就像发现影响DC的修饰曾经并仍在继续做的那样。因此，我们想要研究这一新颖的修饰。生物体的每个细胞都有相同的DNA。然而，分子修饰确保了即使每种细胞类型的DNA是相同的，细胞仍然不同。例如，肝细胞与皮肤细胞不同，具有其他功能。我们最近证实，DA修饰在不同的细胞类型之间是不同的。这表明这种新的修饰可能是不同细胞类型之间观察到的差异的原因。为了更好地理解新的DA修饰，我们将描述和比较DA修饰在不同细胞类型中的位置。通过研究生物体发育早期的这种修饰，我们将更好地理解这种新的修饰是如何在分子水平上建立和调节的。出于伦理方面的考虑，关于人类发展的实验无法进行。然而，为了理解潜在的分子事件，研究人员使用了具有相似和保守的分子机制的动物模型生物。在我们的案例中，我们使用青蛙，这是一种常用的模式生物来研究生物体的发育和不同细胞类型之间的差异。最终，我们希望我们的研究将导致更好地理解为什么不同的细胞类型尽管具有相同的遗传指令，但却是不同的。未来，这些信息可以用于医疗目的，并用于组织替代疗法的器官生成。考虑到影响DC的修饰中的任何错误都可能导致各种疾病，如癌症，很可能新型修饰DA的错误调节也可能导致健康缺陷。因此，研究这种新的DA修饰是至关重要的，因为这有可能打开目前未知的疾病原因的知识。这些知识对于为新的和更好的未来药物疗法铺平道路，最终造福人类健康至关重要。

项目成果

Identification of Methylated Deoxyadenosines in Genomic DNA by dA6m DNA Immunoprecipitation.

• DOI: 10.21769/bioprotoc.1990
• 发表时间: 2016-11
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Magdalena J. Koziol;C. Bradshaw;George E. Allen;Ana S. H. Costa;C. Frezza

Bioinformatics challenges and perspectives when studying the effect of epigenetic modifications on alternative splicing

研究表观遗传修饰对选择性剪接的影响时的生物信息学挑战和观点

• DOI: 10.17863/cam.22044
• 发表时间: 2018
• 作者: Koziol M

Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications.

• DOI: 10.1038/nsmb.3145
• 发表时间: 2016-01
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: Koziol MJ;Bradshaw CR;Allen GE;Costa ASH;Frezza C;Gurdon JB
• 通讯作者: Gurdon JB

Bioinformatics challenges and perspectives when studying the effect of epigenetic modifications on alternative splicing.

• DOI: 10.1098/rstb.2017.0073
• 发表时间: 2018-06-05
• 期刊: Philosophical transactions of the Royal Society of London. Series B, Biological sciences
• 作者: Pacini C;Koziol MJ
• 通讯作者: Koziol MJ

Characteristics and homogeneity of N6-methylation in human genomes.

人类基因组中 N6-甲基化的特征和同质性。

• DOI: 10.1038/s41598-019-41601-7
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Pacini CE