Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming

Derek K. Smith, Jianjing Yang, Meng Lu Liu, Chun Li Zhang

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Pro-neural transcription factors and small molecules can induce the reprogramming of fibroblasts into functional neurons; however, the immediate-early molecular events that catalyze this conversion have not been well defined. We previously demonstrated that neurogenin 2 (NEUROG2), forskolin (F), and dorsomorphin (D) can reprogram fibroblasts into functional neurons with high efficiency. Here, we used this model to define the genetic and epigenetic events that initiate an acquisition of neuronal identity. We demonstrate that NEUROG2 is a pioneer factor, FD enhances chromatin accessibility and H3K27 acetylation, and synergistic transcription activated by these factors is essential to successful reprogramming. CREB1 promotes neuron survival and acts with NEUROG2 to upregulate SOX4, which co-activates NEUROD1 and NEUROD4. In addition, SOX4 targets SWI/SNF subunits and SOX4 knockdown results in extensive loss of open chromatin and abolishes reprogramming. Applying these insights, adult human glioblastoma cell and skin fibroblast reprogramming can be improved using SOX4 or chromatin-modifying chemicals.

Original languageEnglish (US)
Pages (from-to)955-969
Number of pages15
JournalStem Cell Reports
Volume7
Issue number5
DOIs
StatePublished - Nov 8 2016

Keywords

  • ATAC-seq
  • CREB1
  • ChIP-seq
  • NEUROG2
  • RNA-seq
  • SOX4
  • SWI/SNF
  • reprogramming
  • small molecules
  • transdifferentiation

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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