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，一个由母亲遗传，另一个由父亲遗传。对于大多数基因来说，这两个拷贝都是活跃的。然而，有少数基因（约 100 个）受到精细调控，并且仅从母本或父本拷贝中表达。这些基因被称为“印记”基因；它们受到一段DNA序列的调节，该序列带有识别其亲本来源的印记。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。印记基因的失调会导致许多严重的疾病综合症，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加快有关。通常，在通过辅助生殖技术（例如 IVF）受孕的婴儿中更常见地观察到印记基因疾病，这要么是由于潜在的不孕问题，要么是手术的结果。印记基因的调节教会了我们关于活动状态如何的关键原则。我们整个基因组的一部分都受到控制。因此，对印记基因的研究有助于我们全面了解基因在最基本的生物过程中如何开启或关闭。这一研究领域通常被称为“表观遗传学”，因为它涉及对 DNA 序列进行的修饰，调节 DNA 压缩，从而调节基因活性状态，而不改变 DNA 序列本身。我们已经确定了控制印记的全新参与者。基因调控，一种称为 Parp1 的具有酶功能的 DNA 相关蛋白。与之前研究的任何其他因子不同，Parp1 影响所有印记控制元件，因此我们认为它构成了印记基因调控中最核心的角色。Parp1 是一个与许多不同功能相关的因子，其中一些功能取决于其结合DNA 的能力，其酶活性的其他能力，以及两者的组合的其他能力。有趣的是，Parp1 研究最充分的作用之一是在 DNA 修复过程中，正是这种功能使其成为癌症治疗中的重要靶点。事实上，Parp1 的化学抑制剂目前正在针对乳腺癌的临床试验中进行测试。当前的提案旨在研究 Parp1 在印记基因调控中功能的精确机制。这包括详细的分子解剖，包括 Parp1 如何在印记控制区域维持正常的亲本定义标记、它与哪些因素相互作用以及它以何种精确能力发挥这一作用。此外，还将进行全面的分析，研究 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记基因的表观遗传调控提供基本见解。因此，它对于印记疾病、人类不孕症及其治疗程序以及对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途径。由于 Parp1 在细胞中具有多方面的功能，最详细地了解其在表观遗传基因调控中的作用对于设计副作用最小的有针对性的干预策略至关重要，以便在未来利用这些临床途径。

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.

• 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