MicroRNAs Induce a Permissive Chromatin Environment that Enables Neuronal Subtype-Specific Reprogramming of Adult Human Fibroblasts

Cell Stem Cell. 2017 Sep 7;21(3):332-348.e9. doi: 10.1016/j.stem.2017.08.002.


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.

Keywords: DNA methylation; cell fate; chromatin accessibility; chromatin remodeling; direct reprogramming; epigenetics; human neurons; microRNA; motor neurons; neurogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Lineage / genetics
  • Cells, Cultured
  • Cellular Reprogramming* / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly / genetics
  • DNA Methylation / genetics
  • Electrophysiological Phenomena
  • Epigenesis, Genetic
  • Fibroblasts / cytology*
  • Gene Expression Profiling
  • Heterochromatin / metabolism
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Neurogenesis / genetics
  • Neurons / cytology*
  • Neurons / metabolism
  • Spinal Cord / cytology
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation / genetics


  • Chromatin
  • Heterochromatin
  • MicroRNAs