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Assessing the impact of endogenous retroviruses on trophoblast gene regulation

评估内源性逆转录病毒对滋养层基因调控的影响

基本信息

批准号：
BB/T000031/1
负责人：
Miguel Branco
金额：
$ 63.71万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FT000031%2F1
关键词：
Assessing impact endogenous retroviruses trophoblast

项目摘要

Throughout evolution, retroviruses invaded virtually all mammals and became integrated within their genomes. Although these so-called endogenous retroviruses (ERVs) lost their ability to produce viral particles, for a while they could still self-replicate within genomes and be passed on to the next generation. Eventually, most became inactive and could not expand further. Currently there are no known active ERVs in humans and only a relatively small number remain active in mice. Nevertheless, ERVs make up ~8% of the mouse and human genomes.It is thought that most ERVs serve no particular purpose. However, a small subset has been 'domesticated' by the species that host them to perform essential functions. Some have turned into genes, which produce proteins involved in, e.g., immunity and placental development. Others became important regulators of existing genes. That means that certain ERVs can determine whether a given gene is 'on' or 'off'. However, only few examples of this are known to date, and it remains unclear how important ERVs are for the regulation of gene activity.One particular place where ERVs seem to be important is in the placenta. Placental shape and structure varies extensively between different mammals, and it is thought that these differences might come, at least in part, from the influence that ERVs have on gene activity. In this proposal we aim to test this hypothesis by comparing how ERVs affect gene activity in the placenta of mice, rats and humans. First, we will look for differences in the location of ERVs between these species and how it correlates with gene activity in the placenta. This will tell us which ERVs are likely to be important. Next, we will test for causal relationships between ERVs and gene activity by manipulating selected ERVs with molecular tools. We will take several approaches, first inactivating multiple ERVs simultaneously, then removing individual ERVs from the genome. We will test whether these experiments resulted in genes turning 'on' or 'off' and ultimately, any change in the behaviour of placental cells. This proposal will provide clues as to whether ERVs may have played a role in placental evolution, and potentially impact on reproductive success.

在整个进化过程中，逆转录病毒几乎入侵了所有哺乳动物并整合到它们的基因组中。尽管这些所谓的内源性逆转录病毒（ERV）失去了产生病毒颗粒的能力，但在一段时间内它们仍然可以在基因组内自我复制并传递给下一代。最终，大多数都变得不活跃并且无法进一步扩张。目前，人类中尚无已知的活性 ERV，只有相对较少的 ERV 在小鼠中保持活性。然而，ERV 约占小鼠和人类基因组的 8%。人们认为大多数 ERV 没有特殊用途。然而，一小部分已被承载它们以执行基本功能的物种“驯化”。有些已经转化为基因，产生参与免疫和胎盘发育等的蛋白质。其他人则成为现有基因的重要调节者。这意味着某些 ERV 可以确定给定基因是“开启”还是“关闭”。然而，迄今为止，我们只知道很少的例子，而且还不清楚 ERV 对基因活性的调节有多重要。ERV 似乎很重要的一个特殊地方是胎盘。不同哺乳动物的胎盘形状和结构差异很大，人们认为这些差异可能至少部分来自 ERV 对基因活性的影响。在本提案中，我们旨在通过比较 ERV 如何影响小鼠、大鼠和人类胎盘中的基因活性来检验这一假设。首先，我们将寻找这些物种之间 ERV 位置的差异以及它与胎盘中基因活性的关系。这将告诉我们哪些 ERV 可能很重要。接下来，我们将通过使用分子工具操纵选定的 ERV 来测试 ERV 与基因活性之间的因果关系。我们将采取多种方法，首先同时灭活多个 ERV，然后从基因组中去除单个 ERV。我们将测试这些实验是否导致基因“开启”或“关闭”，以及最终胎盘细胞行为的任何变化。该提案将为 ERV 是否在胎盘进化中发挥作用以及对生殖成功的潜在影响提供线索。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function.

DOI：
10.1038/s41594-023-01016-5
发表时间：
2023-07
期刊：
NATURE STRUCTURAL & MOLECULAR BIOLOGY
影响因子：
16.8
作者：
Pal, Debosree;Patel, Manthan;Boulet, Fanny;Sundarraj, Jayakumar;Grant, Olivia A.;Branco, Miguel R.;Basu, Srinjan;Santos, Silvia D. M.;Zabet, Nicolae Radu;Scaffidi, Paola;Pradeepa, Madapura M.
通讯作者：
Pradeepa, Madapura M.

H4K16ac activates the transcription of transposable elements and contributes to their cis-regulatory function

H4K16ac 激活转座元件的转录并有助于其顺式调节功能

DOI：
10.1101/2022.04.29.488986
发表时间：
2022
期刊：
影响因子：
0
作者：
Pal D
通讯作者：
Pal D

Vitamin C activates young LINE-1 elements in mouse embryonic stem cells via H3K9me3 demethylation.

维生素C通过H3K9ME3脱甲基化激活小鼠胚胎干细胞中的年轻线1元素。

DOI：
10.1186/s13072-023-00514-6
发表时间：
2023-10-16
期刊：
Epigenetics & chromatin
影响因子：
3.9
作者：
通讯作者：

Regulation of human trophoblast gene expression by endogenous retroviruses

内源性逆转录病毒对人滋养层基因表达的调节

DOI：
10.1101/2022.04.26.489485
发表时间：
2022
期刊：
影响因子：
0
作者：
Frost J
通讯作者：
Frost J

Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit.

DOI：
10.7554/elife.71094
发表时间：
2022-03-08
期刊：
eLife
影响因子：
7.7
作者：
Ashley B;Simner C;Manousopoulou A;Jenkinson C;Hey F;Frost JM;Rezwan FI;White CH;Lofthouse EM;Hyde E;Cooke LDF;Barton S;Mahon P;Curtis EM;Moon RJ;Crozier SR;Inskip HM;Godfrey KM;Holloway JW;Cooper C;Jones KS;Lewis RM;Hewison M;Garbis SDD;Branco MR;Harvey NC;Cleal JK
通讯作者：
Cleal JK