Abstract：
Animal longevity is a function of global vital organ functionality and, consequently, a complex polygenic trait. Yet, monogenic regulators controlling overall or organ-specific ageing exist, owing their conservation to their function in growth and development. Here, by using pathway analysis combined with wet-biology methods on several dynamic timelines, we identified Hnf1a as a novel master regulator of the maturation and ageing in the adult pancreatic islet during the first year of life. Conditional transgenic mice bearing suboptimal levels of this transcription factor in the pancreatic islets displayed age-dependent changes, with a profile echoing precocious maturation. Additionally, the comparative pathway analysis revealed a link between Hnf1a age-dependent regulation and immune signaling, which was confirmed in the ageing timeline of an overly immunodeficient mouse model. Last, the global proteome analysis of human islets spanning three decades of life largely backed the age-specific regulation observed in mice. Collectively, our results suggest a novel role of Hnf1a as a monogenic regulator of the maturation and ageing process in the pancreatic islet via a direct or indirect regulatory loop with immune signaling.
摘要：
动物寿命是全球重要器官功能的功能，因此,复杂的多基因性状。然而，存在控制整体或器官特异性衰老的单基因调控因子，由于它们的保护，它们在生长和发展中的作用。这里,通过在几个动态时间表上使用途径分析与湿生物学方法相结合，我们确定Hnf1a是成年胰岛在出生后第一年成熟和衰老的新型主要调节因子。胰岛中这种转录因子水平欠佳的条件转基因小鼠表现出年龄依赖性变化，轮廓呼应性早熟。此外,比较途径分析揭示了Hnf1a年龄依赖性调节和免疫信号之间的联系，这在过度免疫缺陷小鼠模型的衰老时间表中得到了证实。最后,对人类胰岛长达30年的全球蛋白质组分析在很大程度上支持了在小鼠中观察到的年龄特异性调控。总的来说，我们的研究结果表明,Hnf1a作为胰岛成熟和衰老过程的单基因调节因子,通过一个直接或间接的免疫信号调节环发挥新的作用.
