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.
McCoy, Matthew J. and Cates, Kitra and Liu, Yangjian and Abernathy, Daniel G. and Zhang, Bo and Liu, Shaopeng and Gontarz, Paul and Kim, Woo Kyung and Chen, Shawei and Kong, Wenjun and Gabel, Harrison W. and Morris, Samantha A. and Yoo, Andrew, Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs (November 12, 2019). Available at SSRN: https://ssrn.com/abstract=3485473 or http://dx.doi.org/10.2139/ssrn.3485473
This version of the paper has not been formally peer reviewed.
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