The Pereira lab publishes “Canonical and isomiR products of miR-142 enhance dendritic cell reprogramming” in Cell Reports

We are thrilled to announce the publication of our article “Canonical and isomiR products of miR-142 enhance dendritic cell reprogramming” in Cell Reports.

MicroRNAs (miRNAs) regulate gene expression by targeting mRNA transcripts and generate isoforms (isomiRs) with distinct target specificity. The role of miRNAs and isomiRs in cellular reprogramming and immune cell specification remains poorly understood. In this study, we used direct type 1 conventional dendritic cell (cDC1) reprogramming as a model to investigate how canonical miRNAs and isomiRs contribute to these processes.

Through a lentiviral screen of 15 primary miRNA (pri-miRNA) candidates, we identified miR-124 and miR-142 as facilitators of cDC1 reprogramming, an effect conserved across mouse and human systems. Yet, our analysis revealed distinct roles for these miRNAs: miR-124 increased the proportion of reprogrammed cells and miR-142 reinforced cDC1 identity. We then investigated the mechanisms underlying the effects of miR-124 and miR-142 through transcriptomic, chromatin accessibility, and proteomic analyses. We found that miR-124 promotes early reprogramming through broad transcriptional remodeling, while miR-142 represses fibroblast identity and activates cDC1-specific programs, highlighted by enhanced XCR1 expression, antigen presentation, and IFN-λ secretion. 

Next, we followed by determining the contribution of canonical and non-canonical miRNA products to cDC1 reprogramming. While miR-124-3p recapitulated the effects of lentiviral pri-miRNA-124, cooperating with PIB during the initial stages of cDC1 reprogramming, non-canonical miR-142 variants showed cooperative effects in increasing cDC1 reprogramming efficiency and fidelity. We further identified TGFBR1 as a miR-142-regulated barrier to cDC1 reprogramming. 

In vivo,  the miR-142 mimic cocktail enhanced cDC1 reprogramming-elicited anti-tumor immunity. Finally, we demonstrated that combined mRNA-miRNA delivery initiates non-viral RNA reprogramming, with miR-124-3p enabling transcriptional remodeling and miR-142 mimics fine-tuning cDC1 reprogramming. 

Led by Nejc Arh, together with Pereira Lab members Ilia Kurochkin and Beatriz Lourenço Vaz,  this work defines the role of miRNA isoform diversity in the regulation of cell fate transitions. From a translational perspective, these results show the potential of RNA-based reprogramming strategies, establishing the foundation for safer and more scalable cancer immunotherapies.

We would like to thank our collaborators at Asgard Therapeutics, as well as Darja Schaefer (Hannover Medical School, Germany) and Carol Geukens. We would also like to acknowledge Clinical Genomics Lund, SciLifeLab, the Center for Translational Genomics (Lund University), and the Lund Stem Cell Center Proteomics facility. This work was supported by the European Research Council (ERC) and the European Innovation Council (EIC), Horizon Europe, NextGenerationEU, Cancerfonden, Swedish Research Council, Novo Nordisk Fonden, Cancer Research Institute, Knut and Alice Wallenberg Foundation, FCT, the Medical Faculty at Lund University, and Region Skåne.

Click here for the full article!