An efficient framework to decipher microRNA regulatory programs applied to T cells.

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.