MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that have crucial roles in regulating gene expression. Increasing evidence supports a role for miRNAs in many human diseases, including cancer and autoimmune disorders. The function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies for several diseases. In this Review we summarize our current knowledge of the design and performance of chemically modified miRNA-targeting antisense oligonucleotides, discuss various in vivo delivery strategies and analyse ongoing challenges to ensure the specificity and efficacy of therapeutic oligonucleotides in vivo. Finally, we review current progress on the clinical development of miRNA-targeting therapeutics.

Significance Genome-wide identification of changes in the expression of large intergenic noncoding RNAs (lincRNAs) in a classical model of innate immune cell activation revealed a panel of 159 lincRNAs that were highly modulated in stimulated THP1 macrophages. One of the lincRNAs, named TNFα and heterogenous nuclear ribonucleoprotein L (hnRNPL) related immunoregulatory LincRNA (THRIL), was essential for induction of TNFα, functions through a ribonucleoprotein (RNP) complex with hnRNPL, and plays an important role as regulator of physiological and pathological inflammatory immune responses.

SUMMARY Here, we generated the first genome-scale shRNA library targeting lincRNAs in the mouse. We performed an unbiased loss-of-function study in mouse embryonic stem cells (mESCs) and identified 20 novel lincRNAs involved in the maintenance of pluripotency. Among these, TUNA (Tcl1 Upstream Neuron-Associated lincRNA), was required for pluripotency and formed a complex with three RNA-binding proteins (RBPs). The TUNA–RBP complex was detected at the promoters of Nanog, Sox2, and Fgf4, and knockdown of TUNA or the individual RBPs inhibited neural differentiation of mESCs. TUNA showed striking evolutionary conservation of both sequence and central nervous system-restricted expression in vertebrates. Accordingly, knockdown of tuna in zebrafish caused impaired locomotor function, and TUNA expression in the brains of Huntington’s patients was significantly associated with disease grade. Our results suggest that the lincRNA TUNA plays a vital role in pluripotency and neural differentiation of ESCs and is associated with neurological function of adult vertebrates.

Small RNA-mediated regulation of iPS cell generationThe generation of induced pluripotent stem cells is limited by the low reprogramming efficiency of somatic cells. Here, three clusters of miRNAs are shown to enhance reprogramming efficiency by targeting the TGF-β and p53 pathways, which inhibit the process.