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 lineage-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. Abernathy et al. show that widespread epigenetic changes underlie miRNA-mediated direct reprogramming of primary adult human fibroblasts into neurons, revealing modular synergism between miRNAs and transcription factors to allow lineage-specific neuronal reprogramming. This work provides a platform for generating distinct subtypes of human neurons from patients.

Original languageEnglish
Pages (from-to)332-348.e9
JournalCell Stem Cell
Issue number3
StatePublished - Sep 7 2017


  • DNA methylation
  • cell fate
  • chromatin accessibility
  • chromatin remodeling
  • direct reprogramming
  • epigenetics
  • human neurons
  • microRNA
  • motor neurons
  • neurogenesis


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