Sensing of miRNA/ssDNA hybrid by AGO2 for Enhancing Gene Transcription

We found that AGO2 suspends the formation of miRNA-single stranded (ss) DNA hybrid due to the high affinity interaction of AGO2-miRNA, being different from canonical miRNA guidance of AGO2 loading for mRNA. By this mechanism, we demonstrated that NamiRNA miR-1246 could promote MMP1 gene transcription to induce osteosarcoma cell metastasis. The observed metastasis features can be also extended to the transmission of miR-1246 enriched and carried by extracellular vesicles (EVs) to induce metastasis phenotypes of benign osteosarcoma cells. Collectively, we reveal that AGO2 senses and stabilizes miRNA-enhancer hybrids/loops to activate global gene expression and elucidate EV-carried miR-1246 plays important biological function to facilitate tumor metastasis. Overall design: 1). Examination of H3K27ac and H3K4me1 histone modifications and AGO2 enrichment alterations in MNNG cells after overexpressing miR-1246; 2). mRNA profiles of MNNG cells after overexpressing miR-1246