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

PARP1 对于维持印记控制区域的表观遗传特征至关重要

• 批准号: MR/L00027X/1
• 负责人: Myriam Hemberger
• 金额: $ 69.99万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL00027X%2F1
• 关键词: PARP1; essential; maintain; epigenetic; hallmarks

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.

我们身体的细胞包含每个基因的两个副本，一个由母亲继承，一个由父亲继承。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）是精确调控的，并且仅从母本或父本拷贝表达。这些基因被称为“印记”基因;它们受到一段DNA序列的调控，该序列携带识别其起源父母的印记。印记基因对于怀孕期间婴儿及其胎盘的正常发育以及出生后和成人的健康至关重要。印记基因的失调导致许多严重的疾病综合征，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。通常情况下，印记基因疾病更频繁地在通过辅助生殖技术（如IVF）受孕的婴儿中观察到，无论是因为潜在的不孕问题还是程序的结果。印记基因的调节告诉我们整个基因组的活动状态是如何控制的关键原则。因此，对印记基因的研究有助于我们全面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”，因为它涉及对DNA序列的修饰，这些修饰调节DNA压缩，从而调节基因活性状态，而不改变DNA序列本身。我们已经确定了一种全新的控制印迹基因调控的参与者，一种具有酶功能的DNA相关蛋白，称为Parp 1。与以往研究的任何其他因子不同，Parp 1影响所有的印迹控制元件，因此我们认为它构成了印迹基因调控中最核心的参与者。Parp 1是一个与许多不同功能相关的因子，其中一些依赖于其与DNA的结合能力，另一些依赖于其酶活性，还有一些依赖于两者的组合。有趣的是，Parp 1的最佳研究角色之一是在DNA修复过程中，正是这种功能使其成为癌症治疗中的一个突出目标。事实上，Parp 1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Parp 1在印记基因调控中的精确机制。这包括一个详细的分子解剖Parp 1如何保持正常的父母的起源定义标记在印记控制区，什么因素，它与和它发挥这种作用的精确能力。此外，将进行全面的分析，调查的意义和后果的Parp 1删除在发育和生理contextual.This工作将提供基本的见解，我们的理解印迹基因的表观遗传调控。因此，它与印记疾病、人类不育症及其治疗程序以及癌症发展的表观遗传贡献具有高度的医学相关性。这些知识为这些领域的前瞻性治疗开辟了新的途径。由于Parp 1在细胞中的多方面功能，对其在表观遗传基因调控中的作用的最详细的了解对于设计具有最小副作用的靶向干预策略以在未来利用这些临床途径至关重要。

项目成果

Maternal DNA Methylation Regulates Early Trophoblast Development.

• DOI: 10.1016/j.devcel.2015.12.027
• 发表时间: 2016-01-25
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Branco MR;King M;Perez-Garcia V;Bogutz AB;Caley M;Fineberg E;Lefebvre L;Cook SJ;Dean W;Hemberger M;Reik W
• 通讯作者: Reik W

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.

• DOI: 10.1016/j.cell.2015.12.025
• 发表时间: 2016-01-28
• 期刊: Cell
• 影响因子: 64.5
• 作者: Dalgaard K;Landgraf K;Heyne S;Lempradl A;Longinotto J;Gossens K;Ruf M;Orthofer M;Strogantsev R;Selvaraj M;Lu TT;Casas E;Teperino R;Surani MA;Zvetkova I;Rimmington D;Tung YC;Lam B;Larder R;Yeo GS;O'Rahilly S;Vavouri T;Whitelaw E;Penninger JM;Jenuwein T;Cheung CL;Ferguson-Smith AC;Coll AP;Körner A;Pospisilik JA
• 通讯作者: Pospisilik JA

Epigenetic memory of the first cell fate decision prevents complete ES cell reprogramming into trophoblast.

第一个细胞命运决策的表观遗传记忆可防止ES细胞重编程为滋养细胞。

• DOI: 10.1038/ncomms6538
• 发表时间: 2014-11-26
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Cambuli, Francesco;Murray, Alexander;Dean, Wendy;Dudzinska, Dominika;Krueger, Felix;Andrews, Simon;Senner, Claire E.;Cook, Simon J.;Hemberger, Myriam
• 通讯作者: Hemberger, Myriam

Plet1 is an epigenetically regulated cell surface protein that provides essential cues to direct trophoblast stem cell differentiation.

• DOI: 10.1038/srep25112
• 发表时间: 2016-04-28
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Murray A;Sienerth AR;Hemberger M
• 通讯作者: Hemberger M

ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells.

• DOI: 10.1093/nar/gku591
• 发表时间: 2014-08
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Roper SJ;Chrysanthou S;Senner CE;Sienerth A;Gnan S;Murray A;Masutani M;Latos P;Hemberger M
• 通讯作者: Hemberger M