Isoform Usage as a Distinct Regulatory Layer Driving Nutrient-Responsive Metabolic Adaptation

Transcriptome modulation is essential for metabolic adaptation to nutrient environments. However, the role of isoform usage, a crucial transcriptome component, is not yet fully understood. This study outlines the landscape of isoform usage modulations across major metabolic organs in both mice and monkeys, spanning diverse metabolic states. Our in-depth analysis identifies numerous isoform-usage events, intricately influenced by nutrient challenges and largely independent of gene expression regulation. Comparative analyses of mice and monkeys highlight hundreds of conserved isoform events that exhibit consistent responses to nutrient challenges across species and correlate with human metabolic traits. When analysing splicing factor-binding motifs in nutrient-regulated events, HuR emerges as the predominant orchestrator of the isoform network in adipocytes, which is validated using an adipose tissue-specific knockout and an Ap2-promoter-driven transgenic mouse model. In summary, our results offer a comprehensive perspective on isoform usage in metabolic regulation, setting a platform for future functional inquiries. Refer to individual Series转录组调控（transcriptome modulation）对于代谢适应营养环境至关重要。然而，作为转录组核心组分的异构体使用（isoform usage），其功能尚未得到完全阐释。本研究系统描绘了小鼠与猴体内主要代谢器官中，覆盖多种代谢状态的异构体使用调控全景图谱。本研究通过深入分析，鉴定出大量异构体使用事件：这类事件受营养挑战的复杂调控，且在很大程度上独立于基因表达调控。对小鼠与猴的比较分析揭示了数百个保守异构体事件，这些事件在跨物种间对营养挑战呈现一致响应，并与人类代谢性状显著相关。在分析营养调控事件中的剪接因子结合基序（splicing factor-binding motifs）时，HuR被鉴定为脂肪细胞内异构体调控网络的核心调控因子，该结论通过脂肪组织特异性敲除及Ap2启动子驱动的转基因小鼠模型得到了有效验证。综上，本研究结果为代谢调控中的异构体使用研究提供了全面视角，为后续功能探究搭建了重要研究平台。请参阅各独立Series。