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

本研究项目旨在增加我们对锌对基因表达调控的基本分子机制的理解。据最近估计，多达10%的人类基因可能编码需要锌来稳定其结构或酶功能的蛋白质，这表明锌元素在健康细胞功能中的重要性。锌不能在体内产生，所以它是饮食的重要组成部分，需要微量。在英国，亚临床缺锌可能会导致与免疫功能下降和妊娠结局不佳相关的健康问题。在世界范围内，临床缺锌是一个主要的健康问题，在以锌缺乏和谷物为主的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微量营养素。重要的是，在整个身体水平和单个细胞水平上都要避免锌缺乏和锌过量的情况，否则无法维持正常的生物功能。因此，稳态机制在分子水平上调控参与锌运输、结合和储存的关键基因的表达。调节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）。细胞的机制,通过增加基因的转录表达必须增加水平的存在多余的锌(去除锌从细胞或增加细胞的能力,以缓冲多余的锌)但就很好理解了,尽管感兴趣,多余的锌的机制,通过减少其他基因的转录,参与锌吸收进细胞内或存储锌的释放,是未知的。本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基因编码的调控作用。我们发现该基因通过减少转录而受锌可用性增加的调节，为研究这一过程提供了理想的模型系统。在确定了这一基因调控过程的分子成分后，我们将确定其他基因的调控区域包含相同的元素，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在全球范围内的基因调控。该研究结果将为我们理解细胞锌稳态的基本机制做出重大贡献，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。在膳食锌吸收和锌排泄的特定背景下，研究结果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意义。

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.