Mechanisms targeting epigenetic states in mammals

针对哺乳动物表观遗传状态的机制

• 批准号: BB/R009996/1
• 负责人: Anne Ferguson-Smith
• 金额: $ 66.57万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR009996%2F1
• 关键词: Mechanisms; targeting; epigenetic; states; mammals

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.

我们的小组对哺乳动物的发展感兴趣，尤其是对基因的调节方式感兴趣。我们专注于表观遗传机制，这些机制是指我们的基因沿染色体包装的方式，以使其能够打开或关闭。在人类中，几乎一半的基因组由一遍又一遍地重复的DNA部分组成。它们不类似于对我们细胞很重要的蛋白质编码基因。但是，这些重复的元素具有“跳跃”和整合在整个基因组中的能力，并有可能破坏我们基因的适当调节。 KRAB锌指蛋白（KZFP）的大型蛋白质已经发展为能够通过将抑制性表观遗传态靶向这些重复来使这些移动重复元素保持沉默。因此，人们认为KZFP与移动重复元素并平行地进化以压制其活动。从而显示我们一直在研究的一个KZFP已被证明针对基因组的独特区域，而不仅仅是重复元素。这完全改变了我们对这个家族的理解，因为这表明这些蛋白质演变为具有调节蛋白质编码基因的更专业的功能。在一项初步研究中，我们确定了另一个针对独特区域的KZFP。它是一种在哺乳动物中高度保守的古老蛋白质，这意味着它必须在进化过程中保存下来，因此很可能在哺乳动物中具有重要作用。它在整个小鼠发育和大多数人体组织中也表达。我们确定了其在小鼠细胞中的靶基因，发现这是一个非常不寻常的KZFP。它似乎与大多数其他人的作用不同，并且似乎无法招募与其他人相同的共同因素。看来这不是一个沉默的KZFP，而是相反的，并有助于基因激活。因为该KZFP在哺乳动物中是如此不寻常，并且如此高度保守，所以我们建议使用小鼠模型进一步研究其功能。我们已经产生了用于编码该KZFP的基因突变体的小鼠，因此耗尽了蛋白质。我们将遵循他们的发展，并评估它们的出错以及突变对其生命过程的影响。这将告诉我们这种蛋白质在做什么以及为什么它发展出了异常的特性。我们将通过确定其分子伙伴和IT不同部分的作用来理解该蛋白质的作用。此外，该项目将不仅有助于我们表征哺乳动物中重要的蛋白质，而且还将帮助我们更深入地了解这一KZFP这个大型家族的演变和功能。我们相信，我们将进一步了解这些蛋白质在分子水平上的行为，并将更好地了解表观遗传机制如何针对基因组的特定独特区域。

项目成果

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function

逆转录转座子上自发遗传诱导的表观等位基因塑造宿主基因组功能

• DOI: 10.17863/cam.68881
• 发表时间: 2021
• 作者: Bertozzi T

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.

• DOI: 10.1073/pnas.2017053117
• 发表时间: 2020-12-08
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Bertozzi TM;Elmer JL;Macfarlan TS;Ferguson-Smith AC
• 通讯作者: Ferguson-Smith AC

Genomic properties of variably methylated retrotransposons in mouse

小鼠可变甲基化逆转录转座子的基因组特性

• DOI: 10.1101/2020.10.21.349217
• 发表时间: 2020
• 作者: Elmer J

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans -Acting Modifiers

内源性逆转录病毒的菌株特异性表观遗传调控：反式作用修饰剂的作用

• DOI: 10.17863/cam.55608
• 发表时间: 2020
• 作者: Elmer J

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.

• DOI: 10.7554/elife.65233
• 发表时间: 2021-03-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Bertozzi TM;Takahashi N;Hanin G;Kazachenka A;Ferguson-Smith AC
• 通讯作者: Ferguson-Smith AC