Programming the paternal nucleus for embryonic development

发育生物学中一个有趣的问题是，为什么受精几乎总是导致非常复杂和明确的有机体的发育。在受精时，两个截然不同的高度专业化的细胞--精子和卵子--融合形成胚胎，然后胚胎可以分化成多种细胞类型，形成成年有机体。但是，胚胎如何知道在发育过程中应该启动哪些基因，以及何时启动，以形成高度专门化的细胞呢？事实证明，精子的细胞核中可能含有指示胚胎表达哪些基因以及何时表达的指令。然而，目前还不清楚精子是如何传递这一信息的，以及这些信息的确切性质是什么。我们的研究旨在了解精子是如何准备向胚胎传递有关基因表达和细胞特化的信息。首先，通过比较精子来源的胚胎和精子前体来源的胚胎，我们发现精子来源的胚胎发育速度是前体胚胎的5倍，而且在转录基因方面也比前体胚胎更好。这意味着精子在其成熟过程中从前体获得关于正确的胚胎基因表达的信息。现在，我们希望通过比较精子和精子前体细胞中存在的基因成分，并找出它们之间的差异，来找出这些信息的本质。接下来，我们想看看这种嵌入在基因成分中的父系信息，在胚胎基因激活时是否仍然存在于胚胎中。为了直接测试父系遗传信息的重要性，我们想要改变精子中这些成分与基因的关联方式，然后监测胚胎中的基因表达模式是否发生了变化。最后，我们想要找出鸡蛋因素(来自母亲的因素)是否对阅读父亲的信息很重要。我们相信，我们的成果将对再生医学领域产生重大影响。对于一些人类疾病/损伤，目前除了用健康细胞替代外，还没有适用的治疗方法。为了产生用于替代疗法的细胞，分化的细胞必须首先切换回(重新编程)到类似胚胎的状态。然而，重新编程的频率非常低。这种重新编程的低效很可能是因为体细胞没有通常存在于精子中的指示信息，而这些信息决定了胚胎基因的表达。如果我们知道这些信息的性质，就可以向体细胞提供这些信息，以便纠正重新编程细胞中的基因表达，从而最终希望提高移植细胞的派生效率。此外，已有研究表明，精子中关于胚胎基因表达的不当信息可能与某些男性不育病例有关。因此，我们的研究结果也可能有助于预防/治疗男性不育病例。

One fascinating question in developmental biology is why fertilization almost invariably leads to the development of a very complex and defined organism. At fertilization two distinct highly specialised cells, the sperm and the egg, fuse to give rise to an embryo which can subsequently differentiate into numerous cell types that form an adult organism. But how does the embryo know which genes to switch on and when during the development in order to make these highly specialised cells? It turns out that the sperm may contain within its nucleus instruction to the embryo as to which genes to express and when. However, it is not well understood how the sperm is transmitting this information and what exactly is the nature of the information. Our research aims to understand how the sperm is prepared to deliver to the embryo information about gene expression and cell specialization. First, by comparing embryos derived from sperm and from sperm precursors, we have shown that the sperm-derived embryos develop 5 times better and are also better at transcribing genes than precursor-derived embryos. This means that the sperm acquires the information about correct embryonic gene expression during its maturation from the precursor. Now we want to find out what is the nature of this information by comparing components present on genes in sperm and sperm precursor cells and finding differences between them. Next, we want to see if this paternal information, embedded in the components present on genes, is still present in the embryos at the time of embryonic gene activation. To test directly the importance of the paternally-inherited information, we want to alter the way the components are associated with genes in the sperm and then monitor if the gene expression pattern in the embryo is altered. Last, we would like to find out if egg factors (the factors contributed from the mother) are important to read the paternal information. We believe that our results will have a significant impact on the field of regenerative medicine. For some human diseases/injuries there are currently no treatments applicable, other than a replacement with healthy cells. In order to generate cells for replacement therapies, differentiated cells have to be first switched back (reprogrammed) to an embryonic-like state. However, the frequency of reprogramming is very low. It is likely that this reprogramming inefficiency results from the fact that the somatic cell does not have the instructive information that is normally present in sperm and that dictates the expression of embryonic genes. If we know the nature of the information, one can then provide a somatic cell with such information in order to correct gene expression in reprogrammed cells, and therefore ultimately hope to increase the efficiency of derivation of cells for transplantation. Additionally, it has been shown that improper information about embryonic gene expression in the sperm can be associated with some cases of male infertility. Therefore, the outcome of our research may also help to prevent/treat male infertility cases.