Virus manipulation of host non-coding RNA regulatory networks

宿主非编码RNA调控网络的病毒操纵

• 批准号: BB/T00021X/1
• 负责人: Adrian Whitehouse
• 金额: $ 80.67万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FT00021X%2F1
• 关键词: Virus; manipulation; host; non; coding

It has been known for some years that only ~2% of the human genome encodes for proteins, whereas ~80% is actively transcribed into RNAs with no obvious coding capacities, known as non-coding RNAs (ncRNAs). The importance of this non-coding transcriptome is emphasised due to the fact that ncRNAs are frequently altered in many human diseases, including aging, cancer, auto-immunity and infections. Functional studies have shown that ncRNAs are critical regulators of gene expression. For example, a group of short ncRNAs known as microRNAs (miRNAs), modulate gene expression by binding to their target protein coding transcript, which leads either to the transcript's translation repression, cleavage or decay. As such, research in this area has mainly focussed on identifying the interaction between specific miRNAs and their target transcript(s). However, emerging evidence now suggests the existence of an unexpected interplay between different ncRNAs that strongly influences, for example, how a miRNA can bind to its target. In this case, other ncRNA species, such as circular RNAs and other long ncRNAs, function as competing endogenous RNAs, interacting with miRNAs to sponge or decoy the miRNA, thus inhibiting the miRNA from binding to the target mRNA and preventing its repression. As such, this network of ncRNA-ncRNA interactions can have a profound effect on the regulation of gene expression in many cellular processes.We have exciting preliminary data suggesting that a herpesviruses has evolved ways to manipulate these ncRNA regulatory networks to enhance virus gene expression and modulate the host response to infection. We have demonstrated that during herpesvirus infection several circular RNAs are upregulated whereas the majority of dysregulated miRNAs are downregulated. This suggests that these virus-induced circular RNAs could sponge specific miRNAs to outcompete their binding to target protein coding transcripts and prevent their repression or degradation. We now aim to further investigate these observations and identify the interplay between ncRNA species and their associated regulatory networks which are manipulated by the virus. Furthermore, we will determine why these regulatory networks are altered during infection by determining the role of the target protein-coding transcripts that are aberrantly expressed due to the manipulation of their respective networks. Moreover, we will investigate novel mechanisms of how a virus enhances circular RNA levels during infection. Finally, we have identified a group of miRNAs that in contrast to the majority of downregulated miRNAs are actually increased during infection, which suggests the virus enhances their production to repress or degrade cellular transcripts which are probably detrimental to virus infection. We will determine how the viruses upregulates these miRNAs and also determine the inhibitory role of their target mRNAs in virus replication.In summary, this project will identify novel ways a virus can manipulate the host cell to enhance its own replication and provide a better understanding how the interplay between different ncRNA species can regulate gene expression. A better knowledge of these fundamental processes has the potential for far reaching impacts on our understanding of cell and developmental biology processes, the development of human disease and provide new strategies for therapeutic interventions of important human pathogens.

多年来，人们已经知道，人类基因组中只有约2%的蛋白质编码，而约80%的蛋白质被主动转录成没有明显编码能力的RNA，称为非编码RNA（ncRNA）。由于ncRNA在许多人类疾病中经常发生改变，包括衰老，癌症，自身免疫和感染，因此强调了这种非编码转录组的重要性。功能研究表明，ncRNA是基因表达的关键调节因子。例如，一组称为microRNA（miRNA）的短ncRNA通过与其靶蛋白编码转录物结合来调节基因表达，这导致转录物的翻译抑制、切割或降解。因此，该领域的研究主要集中在鉴定特定miRNA与其靶转录物之间的相互作用。然而，新出现的证据表明，不同的ncRNA之间存在着意想不到的相互作用，这种相互作用强烈影响着例如miRNA如何与其靶标结合。在这种情况下，其他ncRNA种类，如环状RNA和其他长ncRNA，作为竞争性内源RNA，与miRNA相互作用以海绵或诱骗miRNA，从而抑制miRNA与靶mRNA结合并防止其抑制。因此，这种ncRNA-ncRNA相互作用网络可以对许多细胞过程中的基因表达调控产生深远的影响。我们有令人兴奋的初步数据表明，疱疹病毒已经进化出操纵这些ncRNA调控网络的方法，以增强病毒基因表达并调节宿主对感染的反应。我们已经证明，在疱疹病毒感染期间，一些环状RNA上调，而大多数失调的miRNA下调。这表明，这些病毒诱导的环状RNA可以海绵特定的miRNA，以胜过它们与靶蛋白编码转录本的结合，并防止它们的抑制或降解。我们现在的目标是进一步研究这些观察结果，并确定ncRNA物种及其相关的调控网络之间的相互作用，这些网络由病毒操纵。此外，我们将确定为什么这些调控网络在感染过程中改变，通过确定目标蛋白编码转录本的作用，这些转录本由于操纵各自的网络而异常表达。此外，我们将研究病毒如何在感染过程中提高环状RNA水平的新机制。最后，我们已经鉴定了一组miRNA，与大多数下调的miRNA相反，它们在感染期间实际上是增加的，这表明病毒增强了它们的产生以抑制或降解可能对病毒感染有害的细胞转录物。我们将确定病毒如何上调这些miRNA，并确定其靶mRNA在病毒复制中的抑制作用。总之，本项目将确定病毒可以操纵宿主细胞以增强其自身复制的新方法，并提供更好地理解不同ncRNA种类之间的相互作用如何调节基因表达。更好地了解这些基本过程有可能对我们理解细胞和发育生物学过程、人类疾病的发展产生深远的影响，并为重要的人类病原体的治疗干预提供新的策略。

项目成果

Dysregulation of the miR-30c/DLL4 axis by circHIPK3 is essential for KSHV lytic replication.

• DOI: 10.15252/embr.202154117
• 发表时间: 2022-05-04
• 期刊: EMBO REPORTS
• 影响因子: 7.7
• 作者: Harper, Katherine L.;Mottram, Timothy J.;Anene, Chinedu A.;Foster, Becky;Patterson, Molly R.;McDonnell, Euan;Macdonald, Andrew;Westhead, David;Whitehouse, Adrian
• 通讯作者: Whitehouse, Adrian

CircHIPK3 dysregulation of the miR-30c/DLL4 axis is essential for KSHV lytic replication

• DOI: 10.1101/2021.10.07.463491
• 发表时间: 2021-10
• 期刊: bioRxiv
• 作者: Katherine L. Harper;T. Mottram;C. Anene;Becky Foster;Molly R. Patterson;Euan Mcdonnell;A. Macdonald;D. Westhead;A. Whitehouse

Investigating the structural changes due to adenosine methylation of the Kaposi's sarcoma-associated herpes virus ORF50 transcript.

• DOI: 10.1371/journal.pcbi.1010150
• 发表时间: 2022-05
• 期刊: PLoS computational biology
• 影响因子: 4.3