Characterisation of a novel transcriptional mechanism for the regulation of mammalian gene expression by zinc

锌调节哺乳动物基因表达的新型转录机制的表征

• 批准号: BB/F019637/1
• 负责人: Dianne Ford
• 金额: $ 45.87万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF019637%2F1
• 关键词: Characterisation; novel; transcriptional; mechanism; regulation

This research project is aimed towards increasing our understanding of fundamental molecular mechanisms through which gene expression is regulated in response to zinc. It was estimated recently that up to 10% of all human genes may code for proteins that require zinc to stabilise their structure or for their enzymatic function, indicating the importance of this element in healthy cell function. Zinc can not be produced in the body so it is an essential component of the diet, required in trace quantities. In the UK, subclinical zinc deficiency may contribute to health problems associated with reduced immune function and to poor pregnancy outcome. Worldwide, clinical zinc deficiency, observed in populations subsisting on zinc-poor, cereal-based diets, is a major health problem. The World Health Organisation identifies zinc, along with iron and vitamin A, as a micronutrient for which the population worldwide suffers acute deficit. It is important that conditions of zinc deficiency and zinc excess are avoided at both the whole body level and at the level of the individual cell, otherwise normal biological function can not be maintained. Homeostatic mechanisms, therefore, operate at the molecular level to regulate the expression of key genes involved in zinc transport, binding and storage. Mechanisms through which the expression of a gene can be regulated include changing the rate at which the cell makes RNA copies of that gene (i.e. changing the rate of gene transcription). The mechanism through which the cell increases the transcription of genes that must be expressed at increased levels in the presence of excess zinc (to remove zinc from the cell or to increase the ability of the cell to buffer the excess zinc) is fairly well understood but, in spite of much interest, the mechanism through which excess zinc reduces the transcription of other genes, involved in zinc uptake into the cell or in the release of stored zinc, is unknown. This project will use a range of different molecular techniques to study the regulation by zinc of the gene coding for the human zinc transporter ZnT5. We have found that this gene is regulated by increased zinc availability through reduced transcription, providing an ideal model system on which to study this process. Having identified the molecular components of this gene regulatory process, we will identify other genes whose regulatory regions include the same elements and determine if these are regulated by zinc in the same manner, to establish the extent to which the mechanism we identify is applicable to gene regulation by zinc more globally. The outcomes of the research will make a major contribution to our understanding of the fundamental mechanisms underlying cellular zinc homeostasis and will be of wide interest to researchers in the field of gene regulation in general and the cell biology of zinc in particular. In the specific context of dietary zinc absorption and zinc excretion, the findings will inform more applied research aimed towards optimising zinc nutrition, which has important implications for health worldwide.

本研究旨在加深我们对锌对基因表达调控的基本分子机制的理解。最近估计，在所有人类基因中，多达10%的基因可能编码需要锌来稳定结构或发挥酶功能的蛋白质，这表明了这种元件在健康细胞功能中的重要性。锌不能在体内产生，所以它是饮食中的基本成分，需要微量的锌。在英国，亚临床缺锌可能会导致与免疫功能降低和不良妊娠结局相关的健康问题。在世界范围内，临床缺锌是一个主要的健康问题，在以缺乏锌的谷类饮食为生的人群中观察到。世界卫生组织将锌、铁和维生素A列为全球人口严重缺乏的一种微量营养素。重要的是，在全身和单个细胞水平上都要避免锌缺乏和锌过剩的情况，否则就不能维持正常的生物功能。因此，动态平衡机制在分子水平上调节与锌的运输、结合和储存有关的关键基因的表达。调控基因表达的机制包括改变细胞复制该基因的RNA的速率(即改变基因转录的速率)。细胞通过增加在过量锌存在时必须表达水平的基因的转录(从细胞中去除锌或增加细胞缓冲过剩锌的能力)的机制已经被很好地理解了，但是，尽管人们对过量锌感兴趣，但通过什么机制来减少其他基因的转录，参与锌的吸收到细胞中或参与储存的锌的释放，是未知的。该项目将使用一系列不同的分子技术来研究锌对人类锌转运蛋白ZnT5编码基因的调节。我们发现，该基因通过减少转录增加锌的利用率来调节，这为研究这一过程提供了一个理想的模型系统。在确定了这一基因调控过程的分子组成后，我们将识别其调控区域包含相同元件的其他基因，并确定这些基因是否以相同的方式受到锌的调控，以确定我们所确定的机制在多大程度上适用于锌对基因的调控。这项研究的结果将有助于我们理解细胞锌稳态的基本机制，并将引起基因调控领域的研究人员的广泛兴趣，特别是锌的细胞生物学。在饮食锌吸收和锌排泄的特定背景下，这些发现将为更多旨在优化锌营养的应用研究提供信息，这对全球健康具有重要影响。

项目成果

Analysis of differential gene-regulatory responses to zinc in human intestinal and placental cell lines.

人类肠道和胎盘细胞系对锌的差异基因调节反应的分析。

• DOI: 10.1017/s0007114508094634
• 发表时间: 2009
• 期刊: The British journal of nutrition
• 作者: Jackson KA

Differential subcellular localization of the splice variants of the zinc transporter ZnT5 is dictated by the different C-terminal regions.

• DOI: 10.1371/journal.pone.0023878
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Thornton JK;Taylor KM;Ford D;Valentine RA
• 通讯作者: Valentine RA

Altered expression of ZnT10 in Alzheimer's disease brain.

• DOI: 10.1371/journal.pone.0065475
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Bosomworth HJ;Adlard PA;Ford D;Valentine RA
• 通讯作者: Valentine RA

The zinc finger protein ZNF658 regulates the transcription of genes involved in zinc homeostasis and affects ribosome biogenesis through the zinc transcriptional regulatory element.

• DOI: 10.1128/mcb.01298-14
• 发表时间: 2015-03
• 期刊: Molecular and cellular biology
• 影响因子: 5.3
• 作者: Ogo OA;Tyson J;Cockell SJ;Howard A;Valentine RA;Ford D
• 通讯作者: Ford D