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

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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.