Argonaute nuclear power: nuclear microRNAs control cardiac metabolism in heart failure with preserved ejection fraction

Nuclear functions of miRNAs with relevance for cardiovascular disease. MicroRNAs (miRNAs) are actively transferred to the nucleus in a complex with Argonaute (AGO) proteins via a pathway involving nuclear importin (e.g. Importin 8). Once in the nucleus, AGO-miRNA complexes may act through multiple noncanonical modes of action, including: (A) binding to gene promoters and leading to the assembly of multimolecular complexes, including the TATA-box binding protein (TBP) and RNA polymerase II (Pol II) to initiate gene transcription; (B) interacting with epigenetic enzymes such as the repressive epigenetic writer EZH2 to influence epigenetic marks in nucleosomes. In this case, EZH2 catalyzes the H3K27me3 histone post-translational modification, thus reducing chromatin accessibility and leading to transcriptional repression of target genes; (C) mediating nuclear RNA interference when loaded in RNA-induced silencing complex (RISC)-like molecular complexes containing proteins of the TNRC6 family; (D) being unloaded from AGO proteins and acting as aptamers to regulate multimer protein assembly and ultimately protein function.