Journal
CELL STEM CELL
Volume 21, Issue 3, Pages 332-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2017.08.002
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Funding
- Philip and Sima Needleman graduate student fellowship
- NIH [T32GM081739]
- Children's Discovery Institute
- NIH grant [1U01MH1091330]
- Irma and Norman Braman Endowment
- Suzi and Scott Lustgarten Cancer Endowment
- Andrew B. and Virginia C. Craig Faculty Fellowship endowment
- NIH Director's Innovator Award [DP2NS083372-01]
- Missouri Spinal Cord Injury/Disease Research Program (SCIDRP) [1607]
- Cure Alzheimer's Fund (CAF)
- Presidential Early Career Award for Scientists and Engineers (PECASE) [4DP2NS083372-02]
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Directed reprogramming of human fibroblasts into fully differentiated neurons requires massive changes in epigenetic and transcriptional states. Induction of a chromatin environment permissive for acquiring neuronal subtype identity is therefore a major barrier to fate conversion. Here we show that the brain-enriched miRNAs miR-9/9* and miR-124 (miR-9/9*-124) trigger reconfiguration of chromatin accessibility, DNA methylation, and mRNA expression to induce a default neuronal state. miR-9/9*-124-induced neurons (miNs) are functionally excitable and uncommitted toward specific subtypes but possess open chromatin at neuronal subtype-specific loci, suggesting that such identity can be imparted by additional line-age-specific transcription factors. Consistently, we show that ISL1 and LHX3 selectively drive conversion to a highly homogeneous population of human spinal cord motor neurons. This study shows that modular synergism between miRNAs and neuronal subtype-specific transcription factors can drive lineage-specific neuronal reprogramming, providing a general platform for high-efficiency generation of distinct subtypes of human neurons.
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