Rapid Chromatin Switch in the Direct Reprogramming of Fibroblasts to Neurons Academic Article uri icon

Overview

MeSH Major

  • Cell Differentiation
  • Cerebellum
  • Hippocampus
  • Neurons
  • Proto-Oncogene Proteins B-raf

abstract

  • How transcription factors (TFs) reprogram one cell lineage to another remains unclear. Here, we define chromatin accessibility changes induced by the proneural TF Ascl1 throughout conversion of fibroblasts into induced neuronal (iN) cells. Thousands of genomic loci are affected as early as 12 hr after Ascl1 induction. Surprisingly, over 80% of the accessibility changes occur between days 2 and 5 of the 3-week reprogramming process. This chromatin switch coincides with robust activation of endogenous neuronal TFs and nucleosome phasing of neuronal promoters and enhancers. Subsequent morphological and functional maturation of iN cells is accomplished with relatively little chromatin reconfiguration. By integrating chromatin accessibility and transcriptome changes, we built a network model of dynamic TF regulation during iN cell reprogramming and identified Zfp238, Sox8, and Dlx3 as key TFs downstream of Ascl1. These results reveal a singular, coordinated epigenomic switch during direct reprogramming, in contrast to stepwise cell fate transitions in development.

publication date

  • September 26, 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5646379

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.09.011

PubMed ID

  • 28954238

Additional Document Info

start page

  • 3236

end page

  • 3247

volume

  • 20

number

  • 13