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

我们身体的细胞包含每个基因的两个副本，一个由母亲遗传，一个由父亲遗传。对于大多数基因来说，这两个拷贝都是活跃的。然而，有一小部分基因（约100个）被精确地调控，并且只通过母本或父本拷贝表达。这些基因被称为“印记”基因；它们是由一段DNA序列调控的，这段DNA序列带有识别其母体起源的印记。印迹基因对怀孕期间婴儿及其胎盘的正常发育以及出生后和成年后的健康至关重要。印记基因的失调导致一些严重的疾病综合征，这些综合征通常与发育和生长缺陷、智力迟钝、行为缺陷、血糖失衡等生理问题和肿瘤发展速度增加有关。通常，印迹基因紊乱更常见于通过辅助生殖技术（如体外受精）孕育的婴儿，这要么是因为潜在的不孕问题，要么是手术的结果。对印迹基因的调控教会了我们如何控制整个基因组的活动状态的关键原则。因此，对印迹基因的研究有助于我们了解基因在最主要的生物过程中是如何开启或关闭的。这一研究领域通常被称为“表观遗传学”，因为它研究的是在不改变DNA序列本身的情况下，对DNA序列进行修饰，从而调节DNA压实和基因活性状态。我们已经确定了一个全新的参与者在控制印记基因调控，dna相关蛋白与酶的功能称为Parp1。与之前研究的任何其他因素不同，Parp1影响所有印迹控制元件，因此我们认为它在印迹基因调控中起着最核心的作用。Parp1是一种与许多不同功能相关的因子，其中一些取决于它与DNA的结合能力，另一些取决于它的酶活性，还有一些取决于两者的结合。有趣的是，Parp1在DNA修复过程中的作用是研究得最好的，正是这种功能使其成为癌症治疗的重要靶点。事实上，Parp1的化学抑制剂目前正在乳腺癌的临床试验中进行测试。目前的建议旨在研究Parp1在印迹基因调控中的确切机制。这包括对Parp1如何在印迹控制区域维持正常的母体起源定义标记的详细分子解剖，它与哪些因素相互作用，以及它在何种精确能力中发挥这一作用。此外，将进行全面的分析，调查Parp1缺失在发育和生理背景下的意义和后果。这项工作将为我们理解印迹基因的表观遗传调控提供基本的见解。因此，它对印迹障碍、人类不孕症及其治疗程序以及表观遗传对癌症发展的影响具有很高的医学意义。这些知识为这些领域的前瞻性治疗开辟了新的途径。由于Parp1在细胞中的多面功能，最详细地了解其在表观遗传基因调控中的作用对于设计具有最小副作用的靶向干预策略至关重要，以便在未来开发这些临床途径。

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.