NamiRNA-Enhancer Network: The Changing Era Challenge and Chance of miRNA.

MicroRNAs (miRNAs) systematically orchestrate multiple biological processes via gene regulation in various organisms. Conventionally, miRNAs bind to untranslated regions of mRNAs to modulate gene silencing in the cytoplasm. Recent studies have revealed that a subset of miRNAs located in the nucleus can efficiently activate gene transcription by targeting enhancers, named as Nuclear Activating miRNAs (NamiRNAs). The fundamental principle of this regulatory pattern is that NamiRNAs as "wedges" open double strands of genomic DNA and provide the prerequisite for RNA polymerase II-mediated transcription. Specifically, NamiRNAs bind to their target enhancers and form the hybrids of miRNAs and single-stranded DNA, which are recognized by Argonaute 2 (AGO2) to maintain the single-stranded state. Meanwhile, AGO2 protects these miRNA-DNA hybrids from RNase H-mediated degradation to maintain their stability. Additionally, NamiRNAs induce H3K27ac enrichment at target enhancers and put them into an active state conducive to gene activation. Notably, similar to NamiRNAs, Human Identical Sequences as exogenous small RNAs as critical pathogenic factors for RNA viruses, facilitate infectious disease progression. Collectively, this review systematically elucidates the theory of NamiRNA-Enhancer-mediated Gene Activation in combination with corresponding evidence, summarizes the functions and challenges of NamiRNAs, and discusses their potential in fundamental research and clinical applications.