Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Cell-fate conversion generally presumes the activity of transcription factors to introduce fate programs of the target cell type in the midst of a pre-existing genetic network. Here, we reveal novel insights into cellular reprogramming in which microRNAs, miR-9/9* and miR-124 (miR-9/9*-124), orchestrate direct conversion of human fibroblasts by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. Among the direct target genes of miR-9/9*-124, we identify KLF-family transcription factors whose repression is critical for erasing fibroblast fate. The subsequent upregulation of a small nuclear RNA, RN7SK induces chromatin reconfiguration and neuronal gene activation, pushing the reprogramming cells to a neuronal state and allowing for neuronal maturation and subtype-specification. Our study defines deterministic components in the reprogramming cascade by microRNAs.