miRNA upregulate protein and glycan expression via direct activation in proliferating cells

The dominant paradigm is that miRNA binding to mRNA represses protein expression. Activation by miRNA has been observed in select circumstances (quiescent cells, mitochondria), but is not thought a feature of miRNA action in actively dividing cells. Herein, we comprehensively map the miRNA regulation of -2,6-sialyltransferases ST6GAL1 and ST6GAL2 using a high-throughput assay (miRFluR). We find the majority of miRNA targeting ST6GAL1, the main enzyme controlling -2,6-sialylation, upregulate protein expression. In contrast, those that regulate ST6GAL2 are predominantly downregulatory. We provide evidence that miRNA-mediated upregulation occurs in proliferating cells and is a direct effect. Further, we show that AGO2 and FXR1 are required. Our data expands current understanding of miRNA, providing strong evidence of both upregulatory and downregulatory roles for these non-coding RNA. One-Sentence SummarymiRNA directly activate expression of -2,6-sialyltransferases and sialylation, expanding miRNA actions in dividing cells.