Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis
Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis
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DOI：
10.1073/pnas.1117207108
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发表时间：
2011-12-27
影响因子：
11.1
通讯作者：
Cousins, Robert J.
中科院分区：
文献类型：
--
作者：
Ryu, Moon-Suhn;Langkamp-Henken, Bobbi;Cousins, Robert J.
对疑似缺锌的受试者实施锌干预是全球需求，但由于缺乏可靠的生物标志物而受到限制。为了发现人类锌缺乏的分子特征，将转录组、细胞因子和microRNA分析的组合应用于年轻男性人类受试者的饮食锌消耗/补充方案。伴随着血清锌浓度的降低，与锌稳态相关的颊和血液基因转录的变化与锌耗竭发生。全血RNA的微阵列分析揭示了锌反应基因，特别是那些与细胞周期调控和免疫相关的基因。通过实时荧光定量PCR进一步评估饮食锌缺乏的潜在标签基因的响应。特定血清microRNA对膳食锌缺乏的诊断特性是通过对锌缺乏的急性反应来确定的，这是通过随后的锌补充来逆转的。在低锌摄入后观察到血细胞免疫刺激的TNF α分泌的抑制，并可作为功能性生物标志物。我们的研究结果引入了许多新的候选生物标志物，用于使用各种当代技术进行膳食锌状态评估，并识别在代表当前锌状态评估标志物的血清锌浓度之前发生或具有更高灵敏度的变化。此外，基因网络分析的结果揭示了潜在的临床结果，可归因于次优锌摄入量，包括免疫功能缺陷和癌症易感性。这些通过受控的消耗/补充饮食方案证明，可以鉴定虚假的锌生物标志物并将其应用于评估和干预策略。
Implementation of zinc interventions for subjects suspected of being zinc-deficient is a global need, but is limited due to the absence of reliable biomarkers. To discover molecular signatures of human zinc deficiency, a combination of transcriptome, cytokine, and microRNA analyses was applied to a dietary zinc depletion/repletion protocol with young male human subjects. Concomitant with a decrease in serum zinc concentration, changes in buccal and blood gene transcripts related to zinc homeostasis occurred with zinc depletion. Microarray analyses of whole blood RNA revealed zinc-responsive genes, particularly, those associated with cell cycle regulation and immunity. Responses of potential signature genes of dietary zinc depletion were further assessed by quantitative real-time PCR. The diagnostic properties of specific serum microRNAs for dietary zinc deficiency were identified by acute responses to zinc depletion, which were reversible by subsequent zinc repletion. Depression of immune-stimulated TNF alpha secretion by blood cells was observed after low zinc consumption and may serve as a functional biomarker. Our findings introduce numerous novel candidate biomarkers for dietary zinc status assessment using a variety of contemporary technologies and which identify changes that occur prior to or with greater sensitivity than the serum zinc concentration which represents the current zinc status assessment marker. In addition, the results of gene network analysis reveal potential clinical outcomes attributable to suboptimal zinc intake including immune function defects and predisposition to cancer. These demonstrate through a controlled depletion/repletion dietary protocol that the illusive zinc biomarker(s) can be identified and applied to assessment and intervention strategies.