Genomic imprinting and the epigenetic control of developmental processes

我们体内的所有细胞在基因上都是相同的，包含46条染色体(23对)，我们所有的基因都位于这些染色体中--23条染色体来自我们母亲的卵子，23条来自我们父亲的精子。因此，从受孕开始，一个正常的个体就会有每个基因的两个副本。这个应用程序是关于一种叫做基因组印记的过程。印记导致特定的基因只从母体或父体而不是从两个复制体启动(表达)。这是一个只影响我们大约1%基因的过程。但是，通过印记控制基因剂量在发育过程中很重要，当印记出错时，这会导致生长缺陷、神经综合征和癌症。这项资助探索了印记的调节、功能和进化，以便我们能够更好地了解这些疾病的过程。我们对了解印记表达的机制很感兴趣。是什么使得印记基因从一对染色体中的一条染色体而不是两条染色体中表达出来？这个过程只导致父系遗传或母系遗传的拷贝被表达，这是一种表观遗传过程。表观遗传学意味着‘在遗传学之上’，印记基因的表观遗传状态表现为化学修饰，即只位于一条双亲染色体上的DNA，而不是另一条，导致位于那里的基因在一条染色体上表达，而在另一条染色体上保持不表达。我们的第一个目标是询问是否所有印记基因在一条染色体上完全打开，在另一条染色体上完全关闭，或者是否有些印记基因在两条染色体上都表达，但在一条染色体上表达得更多，在另一条染色体上表达得更少。这对于理解印记的机制以及印记的基因是否比最初认为的更多是很重要的。这对疾病有一定的影响。在我们的第二个目标中，我们感兴趣的是一个特别重要的印记基因(Dlk1)的功能，它不仅能够以印记的方式发挥作用，而且能够像来自双亲染色体的其他基因一样表达。这是一种非凡的基因，其剂量对大脑和身体其他部位也非常重要。事实上，它还调节我们脂肪的发育，并控制新陈代谢。有趣的是，还有一个基因(Dlk2)看起来很像这个(Dlk2)；它从未被印记，是Dlk1的祖先，Dlk1是Dlk2的副本。Dlk2只在大脑中起作用。在这组实验中，我们将研究这两个基因之间的关系，询问一个基因是如何以及为什么从另一个基因进化而来的，为什么一个基因被印记而另一个基因不被印记，以及它们在相同和不同的途径中发挥作用的程度。印迹调控的基因对于控制子宫内的生长发育非常重要，这一点在胎盘中已经得到了广泛的研究，胎盘是印迹基因表达的重要部位。然而，由于重要的营养事件也发生在出生后，我们假设印记基因也调节出生后的营养。在我们的第三个目标中，我们将询问通过乳腺给后代喂奶的能力是否也受到基因组印记的控制。由于乳腺在怀孕、哺乳和断奶期间经历了戏剧性的变化，这些变化很可能是受表观遗传控制的。因此，第三个目标中概述的实验不仅将为乳腺的发育和母婴之间的营养资源交换提供重要的知识，而且可能为我们理解印记过程的功能、机制和进化提供有用的见解。

All the cells in our body are genetically identical and contain 46 chromosomes (23 pairs) where all of our genes are located - 23 chromosomes originally came from our mother's egg and 23 from our father's sperm. Thus, since the time of conception, a normal individual will have two copies of every gene. This application is about a process called Genomic Imprinting. Imprinting causes specific genes to be turned on (expressed) solely from the maternal or from the paternal copy rather than from both copies. It is a process that affects only about 1% of our genes. But control of gene dosage by imprinting is important during development, and when imprinting goes wrong this leads to growth defects, neurological syndromes and cancer. This grant explores the regulation, function and evolution of imprinting, so we can understand these disease processes better.We are interested in understanding mechanisms of imprinted expression. What makes an imprinted gene be expressed from one of the chromosomes in a pair rather than both of them? The process causing only the paternally inherited or the maternally inherited copy to be expressed, is an 'epigenetic' one. Epigenetics means 'on top of genetics' and the epigenetic state at an imprinted gene is manifested as chemical modifications that sit on the DNA at only one parental chromosome and not the other causing the gene located there to be expressed on one of the chromosomes and kept off on the other. Our first aim is designed to ask whether all imprinted genes are fully ON on one chromosome and fully OFF on the other, or whether some imprinted genes are expressed from both chromosomes but more from one chromosome and less from the other. This is important for understanding mechanisms of imprinting and whether more genes are imprinted than originally thought. This has implications for disease. In our second aim, we are interested in focusing on the function of a particularly important imprinted gene (Dlk1) that is able to act not only in an imprinted way, but also be expressed like other genes from both parental chromosomes. This is a remarkable gene whose dosage is very important in the brain and elsewhere in the body too. In fact, it also regulates the development of our fat, and controls metabolism. Interestingly there is another gene that looks very like this one (Dlk2); it is never imprinted and is the ancestor to Dlk1 which arose as a copy of Dlk2. Dlk2 only functions in the brain. In this set of experiments, we will study the relationship between these two genes, asking how and why one evolved from the other, why one is imprinted and the other not, and the extent to which they act in the same and in different pathways. Genes regulated by imprinting are very important for controlling growth and development in the womb and this has been extensively studied in the placenta which is an essential site of imprinted gene expression. However, since important nutritional events happen after birth too, we hypothesize that imprinted genes also regulate postnatal nutrition. In our third aim, we will ask whether the ability to feed milk to offspring via the mammary gland is also controlled by genomic imprinting. Since the mammary gland undergoes dramatic changes during pregnancy, lactation and upon weaning, it is likely that these changes are subject to epigenetic control. Hence the experiments outlined in this third aim will not only provide important knowledge about the development of the mammary gland and the exchange of nutritional resources between mother and baby, but might also provide useful insights into our understanding of the function, mechanism and evolution of the imprinting process.