Zhu Hongya, Ganapathi Sankaran Divya, Smith Norah L, Daly Ciarán W P, Yee Mon Kristel, Tabilas Cybelle, Wissink Erin M, Rudd Brian D, Grimson Andrew
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
Genes Immun. 2025 Aug 18. doi: 10.1038/s41435-025-00351-5.
Naïve CD8 + T cells are heterogenous, with subsets exhibiting divergent kinetics and functions post-activation. MicroRNAs, important mediators of post-transcriptional regulation, contribute to specification of different naïve T cell subsets. However, the microRNA regulatory circuits mediating functional specialization of naïve subsets are poorly understood. Here, we profiled microRNA expression in diverse subsets of naïve CD8 + T cells, revealing significant differences in their microRNA expression landscapes. We developed a novel framework, miR-Inf, to decipher microRNA regulatory programs. miR-Inf features two innovative attributes: (i) an efficient approach based on intron-exon ratios to estimate gene decay rates from a compendium of RNA-seq profiles, in order to better capture microRNA regulatory effects, and (ii) identification of cell-type-specific microRNA targets by integrating decay rate data and microRNA expression data. We applied this framework to identify consequential miRNAs in naïve CD8 + T cell subsets and predicted their subset-specific targets. Our analyses revealed that miR-29, a microRNA known to be important in CD8 + T cells, likely functions by modulating transcripts encoding epigenetic factors, thereby pre-programming different naïve T cell subsets to exhibit different immune responses post-activation. Collectively, our data and broadly applicable framework defined microRNA regulatory circuits across a variety of naïve CD8 + T cell subsets.
初始CD8 + T细胞是异质性的，其亚群在激活后表现出不同的动力学和功能。微小RNA是转录后调控的重要介质，有助于不同初始T细胞亚群的特异性分化。然而，介导初始亚群功能特化的微小RNA调控回路仍知之甚少。在这里，我们分析了初始CD8 + T细胞不同亚群中的微小RNA表达，揭示了它们微小RNA表达图谱的显著差异。我们开发了一个新的框架miR-Inf来破译微小RNA调控程序。miR-Inf具有两个创新特性：（i）一种基于内含子-外显子比率的有效方法，用于从RNA测序图谱汇编中估计基因衰减率，以便更好地捕捉微小RNA调控效应，以及（ii）通过整合衰减率数据和微小RNA表达数据来识别细胞类型特异性微小RNA靶标。我们应用这个框架来识别初始CD8 + T细胞亚群中的重要微小RNA，并预测它们的亚群特异性靶标。我们的分析表明，已知在CD8 + T细胞中起重要作用的微小RNA miR-29，可能通过调节编码表观遗传因子的转录本发挥作用，从而预先设定不同的初始T细胞亚群在激活后表现出不同的免疫反应。总体而言，我们的数据和广泛适用的框架定义了各种初始CD8 + T细胞亚群中的微小RNA调控回路。
