Argonaute and small RNAs in the nucleus: Mediators of gene silencing and activation

RNA molecules are dynamic regulators of gene expression, with duplex RNAs such as siRNAs and saRNAs functioning as versatile effectors that can both silence and activate gene expression through Argonaute (AGO) proteins. While cytoplasmic RNA interference (RNAi) is well established, the mechanisms and outcomes of nuclear RNAi and RNA activation (RNAa) are only emerging. This review integrates recent discoveries on nuclear RNAi and RNAa, outlining how siRNAs can target nuclear long noncoding RNAs, promoter-associated transcripts, and pre-mRNAs to mediate silencing, transcriptional repression, or alternative splicing. Conversely, saRNAs can recruit AGO2 and transcriptional cofactors to activate gene expression through chromatin remodeling and RNA polymerase II engagement. Beyond their mechanistic roles, we highlight the growing therapeutic potential of duplex RNAs, which can be harnessed to selectively silence or activate gene expression, offering new strategies for RNA-based precision medicine.