Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, United States.
Front Endocrinol (Lausanne). 2022 Jul 22;13:955070. doi: 10.3389/fendo.2022.955070. eCollection 2022.
Diurnal oscillation persists throughout the body and plays an essential role in maintaining physiological homeostasis. Disruption of diurnal rhythm contributes to many diseases including type 2 diabetes. The regulatory mechanism of the transcription-translation feedback loop (TTFL) of core clock genes is well-established, while a systematic study across all regulatory layers of gene expression, including gene transcription, RNA translation, and DNA binding protein (DBP) activities, is still lacking. We comprehensively bioinformatics analyzed the rhythmicity of gene transcription, mature RNA abundance, protein abundance and DBP activity using publicly available omic-datasets from mouse livers. We found that the core clock genes, and , persistently retained rhythmicity in all stages, which supported the essential rhythmic function along with the TTFL. Interestingly, there were many layer-specific rhythmic genes playing layer-specific rhythmic functions. The systematic analysis of gene transcription rate, RNA translation efficiency, and post-translation modification of DBP were incorporated to determine the potential mechanisms for layer-specific rhythmic genes. We observed the gene with rhythmic expression in both mature RNA and protein layers were largely due to relatively consistent translation rate. In addition, rhythmic translation rate induced the rhythms of protein whose mature RNA levels were not rhythmic. Further analysis revealed a phosphorylation-mediated and an enhancer RNA-mediated cycling regulation between the corresponding layers. This study presents a global view of the oscillating genes in multiple layers a systematical analysis and indicates the complexity of regulatory mechanisms across different layers for further functional study.
昼夜节律在体内持续存在，对维持生理内稳态起着至关重要的作用。昼夜节律的破坏导致许多疾病，包括 2 型糖尿病。核心时钟基因的转录-翻译反馈环 (TTFL) 的调节机制已经得到很好的建立，而包括基因转录、RNA 翻译和 DNA 结合蛋白 (DBP) 活性在内的所有基因表达调控层的系统研究仍然缺乏。我们使用来自小鼠肝脏的公开可用的组学数据集，全面地进行了生物信息学分析，以研究基因转录、成熟 RNA 丰度、蛋白质丰度和 DBP 活性的节律性。我们发现核心时钟基因、和 ，在所有阶段都持续保持节律性，这支持了 TTFL 的基本节律功能。有趣的是，有许多特定层的节律基因发挥特定层的节律功能。系统分析基因转录率、RNA 翻译效率和 DBP 的翻译后修饰，以确定特定层节律基因的潜在机制。我们观察到在成熟 RNA 和蛋白质层都具有节律表达的基因主要是由于相对一致的翻译率。此外，节律性翻译率诱导了其成熟 RNA 水平无节律的蛋白质的节律。进一步的分析揭示了相应层之间的磷酸化介导和增强子 RNA 介导的循环调节。这项研究提供了多个层面上振荡基因的全景图，对不同层面的调控机制进行了系统分析，并表明了不同层面的调控机制的复杂性，以进行进一步的功能研究。
