Mechanisms targeting epigenetic states in mammals

我们小组对哺乳动物的发育感兴趣，尤其是基因是如何调控的。我们专注于表观遗传机制，这是关于我们的基因如何沿着染色体包装，使它们能够被打开或关闭。在人类中，几乎一半的基因组由反复重复的DNA片段组成。它们与蛋白质编码基因不同，蛋白质编码基因对我们的细胞很重要。然而，这些重复的元件有能力“跳跃”并将自己整合到整个基因组中，从而有可能扰乱我们基因的适当调控。KRAB锌指蛋白(KZFP)是一个蛋白质大家族，它已经进化到能够通过靶向这些重复的抑制性表观遗传状态来沉默这些移动的重复元件。因此，KZFP被认为是与移动的重复元件并行进化的，以抑制其活性。有趣的是，我们一直在研究的一种KZFP被证明针对基因组的独特区域，而不仅仅是重复元件。这完全改变了我们对这个家族的理解，因为它表明这些蛋白质进化成具有更特殊的功能，调节蛋白质编码基因。在初步研究中，我们已经确定了另一个同样针对独特地区的KZFP。它是一种古老的蛋白质，在哺乳动物中高度保守，这意味着它必须在进化过程中得到保存，因此很可能在哺乳动物中发挥重要作用。它也在小鼠发育过程中和大多数人类组织中表达。我们在小鼠细胞中鉴定了它的靶基因，发现这是一个非常不寻常的KZFP。它的行为方式似乎与大多数其他公司不同，似乎无法招募到与其他公司相同的辅助因素。这似乎不是沉默的KZFP，而是起相反作用并有助于基因激活的KZFP。由于KZFP在哺乳动物中是如此不寻常和高度保守，我们建议用小鼠模型进一步研究它的功能。我们已经产生了编码这种KZFP的基因突变的小鼠，因此缺乏这种蛋白质。我们将跟踪他们的发育，评估他们的问题以及突变对他们生命过程的影响。这将告诉我们这种蛋白质在做什么，以及为什么它进化出了不寻常的特性。我们将通过确定KZFP的分子伴侣和不同部分的作用来了解该蛋白的作用。总之，这个项目不仅有助于我们描述哺乳动物中的一个重要蛋白质，也将帮助我们更深入地了解KZFP这个大家族的进化和功能。我们相信，我们将更多地了解这些蛋白质在分子水平上的行为，并将更好地理解表观遗传机制是如何针对基因组的特定独特区域的。

Our group is interested in mammalian development and in particular in how genes are regulated. We focus on epigenetic mechanisms, which are about how our genes are packaged along the chromosome, to make them able to be turned on or off. In human, almost half of the genome is composed of bits of DNA that are repeated over and over again. They do not resemble the protein coding genes that are important for our cells. However, these repetitive elements have the ability to "jump" and integrate themselves all over the genome with the potential to disrupt the proper regulation of our genes. A large family of proteins, the KRAB zinc finger proteins (KZFP), have evolved to be able to silence these mobile repetitive elements by targeting repressive epigenetic states to these repeats. Thus, KZFPs are thought to have evolved in parallel with mobile repetitive elements to repress their activity.Interestingly, one KZFP that we have been studying has been shown to target unique regions of the genome, and not just repeat elements. This has completely changed our understanding of this family, as it suggests that these proteins evolved to have more specialised functions regulating protein-coding genes. In a preliminary study, we have identified another KZFP that also targets unique regions. It is an ancient protein highly conserved in mammals, meaning that it must have been preserved during evolution and so is very likely to have an essential role in mammals. It is also expressed throughout mouse development and in most human tissues. We identified its target genes in mouse cells, and found that this is a very unusual KZFP. It seems to act in a different way than most others, and does not seem to be able to recruit the same co-factor as the others. It appears that this is not a silencing KZFP but one that does the opposite and contributes to gene activation. Because this KZFP is so unusual and so highly conserved in mammals, we propose to investigate its functions further using mice models. We have generated mice that are mutant for the gene encoding this KZFP and hence are depleted of the protein. We will follow their development and assess what is wrong with them and impact of the mutation on their life-course. This will tell us what this protein is doing and why it has evolved its unusual properties. We will aim at understanding the action of this protein by identifying its molecular partners and the role of different parts of it.Overall, this project will not only help us to characterize an important protein in mammals but also it will help us to gain greater insight into the evolution and function of this large family of KZFP. We believe we will learn more about how these proteins behave on the molecular level and will better understand how epigenetic mechanisms are targeted to specific unique regions of the genome.