MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging.
MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging.
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艾姆斯侏儒小鼠肝脏中的 MicroRNA 调节可能有助于延缓衰老。
DOI：
10.1111/j.1474-9726.2009.00529.x
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发表时间：
2010-02
期刊：
影响因子：
7.8
通讯作者：
Wang E
中科院分区：
文献类型：
--
作者：
Bates DJ;Li N;Liang R;Sarojini H;An J;Masternak MM;Bartke A;Wang E
艾姆斯侏儒小鼠以其延缓衰老的显著倾向而闻名。虽然已经取得了显着的进展表明，这种老化表型的结果主要是从内分泌失调，基因表达的转录后调控及其对寿命的影响仍有待探讨。为此，我们提出了第一个全面的研究microRNA微阵列筛选，以确定侏儒特异性的铅microRNA，并探讨其作为关键的分子调控因子指导长寿表型的作用。映射的签名microRNA的反向表达推定的靶基因，然后在原位免疫组织化学染色和体外相关分析，揭示了侏儒小鼠转录后调节中间代谢的关键蛋白，最重要的是生物合成途径，涉及鸟氨酸脱羧酶和亚精胺合酶。在共转染实验中使用3′UTR报告基因构建体的功能测定证实，microRNA-27 a确实抑制了这两种蛋白质的表达，将它们标记为该microRNA在体内的可能靶点。此外，早在两个月大的侏儒小鼠肝脏中就确定了这种microRNA对鸟氨酸脱羧酶的推定抑制作用。总之，我们的研究结果表明，在侏儒小鼠肝脏中检测到的中间代谢的改变方面-谷胱甘肽代谢，尿素循环和多胺生物合成- microRNA-27 a是关键的转录后控制。此外，与其正常的兄弟姐妹相比，侏儒小鼠在调节这些通路以控制其正常性方面表现出领先优势，这可能最终有助于延长其健康寿命和寿命。
The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the posttranscriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA microarray screening to identify dwarf-specific lead microRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype. Mapping the signature microRNAs to the inversely expressed putative target genes, followed by in situ immunohistochemical staining and in vitro correlation assays, reveal that dwarf mice posttranscriptionally regulate key proteins of intermediate metabolism, most importantly the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. Functional assays using 3′UTR reporter constructs in co-transfection experiments confirm that microRNA-27a indeed suppresses the expression of both of these proteins, marking them as probable targets of this microRNA in vivo. Moreover, the putative repressed action of this microRNA on ornithine decarboxylase is identified in dwarf mouse liver as early as two months of age. Taken together, our results show that among the altered aspects of intermediate metabolism detected in the dwarf mouse liver — glutathione metabolism, the urea cycle, and polyamine biosynthesis — microRNA-27a is a key posttranscriptional control. Furthermore, compared to its normal siblings, the dwarf mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended healthspan and longevity.
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影响因子：
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作者：
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