PARP1 is essential to maintain the epigenetic hallmarks of imprinting control regions

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The cells of our body contain two copies of every gene, one inherited by the mother and one by the father. For most genes, both of these copies are active. However, there is a small number of genes (~100) that are exquisitely regulated and expressed either only from the maternal or the paternal copy. These genes are known as 'imprinted' genes; they are regulated by a stretch of DNA sequence that carries an imprint which identifies its parent-of-origin. Imprinted genes are fundamentally important for normal development of the baby and its placenta during pregnancy, as well as for health after birth and of the adult. De-regulation of imprinted genes causes a number of severe disease syndromes commonly associated with developmental and growth defects, mental retardation, behavioural defects, physiological problems such as blood sugar imbalance and an increased rate of tumour development. Often, imprinted gene disorders are more frequently observed in babies conceived by assisted reproductive technologies such as IVF, either because of the underlying infertility problems or as a result of the procedure.The regulation of imprinted genes has taught us key principles about how the activity state of our entire genome is controlled. As such the study of imprinted genes has been instrumental for our general understanding of how genes are switched on or off in the most principal biological processes. This area of research is commonly referred to as 'Epigenetics' as it deals with modifications imposed onto the DNA sequence that regulate DNA compaction and therefore gene activity state without changing the DNA sequence itself.We have identified an entirely novel player in the control of imprinted gene regulation, a DNA-associated protein with enzymatic function called Parp1. Unlike any other factor previously investigated, Parp1 affects all imprinting control elements, and we therefore believe that it constitutes a most central player in imprinted gene regulation.Parp1 is a factor that has been associated with many different functions, some of which depend on its binding capacity to DNA, others to its enzymatic activity, and yet others to combinations of both. Intriguingly, one of the best-studied roles of Parp1 is in DNA repair processes, and it is this function that has made it a prominent target in cancer therapies. Indeed, chemical inhibitors of Parp1 are currently tested in clinical trials for breast cancer.The current proposal aims at investigating the precise mechanism of Parp1 function in imprinted gene regulation. This includes a detailed molecular dissection of how Parp1 maintains the normal parent-of-origin defining mark at imprinting control regions, what factors it interacts with and in which precise capacity it exerts this role. In addition, a comprehensive analysis will be performed that investigates the significance and consequences of Parp1 deletion in a developmental and physiological context.This work will provide fundamental insights into our understanding of the epigenetic regulation of imprinted genes. As such, it is of high medical relevance for imprinting disorders, human infertility and its treatment procedures, and epigenetic contributions to cancer development. This knowledge opens up new avenues towards prospective therapies in these areas. Due to the multi-facetted functions of Parp1 in the cell, a most detailed understanding of its role in epigenetic gene regulation is of utmost importance to devise targeted intervention strategies with minimal side effects in order to exploit these clinical avenues in the future.