Olig2 Targets Chromatin Remodelers to Enhancers to Initiate Oligodendrocyte Differentiation

Cell. 2013 Jan 17;152(1-2):248-61. doi: 10.1016/j.cell.2012.12.006.

Abstract

Establishment of oligodendrocyte identity is crucial for subsequent events of myelination in the CNS. Here, we demonstrate that activation of ATP-dependent SWI/SNF chromatin-remodeling enzyme Smarca4/Brg1 at the differentiation onset is necessary and sufficient to initiate and promote oligodendrocyte lineage progression and maturation. Genome-wide multistage studies by ChIP-seq reveal that oligodendrocyte-lineage determination factor Olig2 functions as a prepatterning factor to direct Smarca4/Brg1 to oligodendrocyte-specific enhancers. Recruitment of Smarca4/Brg1 to distinct subsets of myelination regulatory genes is developmentally regulated. Functional analyses of Smarca4/Brg1 and Olig2 co-occupancy relative to chromatin epigenetic marking uncover stage-specific cis-regulatory elements that predict sets of transcriptional regulators controlling oligodendrocyte differentiation. Together, our results demonstrate that regulation of the functional specificity and activity of a Smarca4/Brg1-dependent chromatin-remodeling complex by Olig2, coupled with transcriptionally linked chromatin modifications, is critical to precisely initiate and establish the transcriptional program that promotes oligodendrocyte differentiation and subsequent myelination of the CNS.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Brain / cytology
  • Cell Differentiation*
  • Cells, Cultured
  • Chromatin Assembly and Disassembly*
  • DNA Helicases / metabolism
  • Enhancer Elements, Genetic*
  • Gene Expression Regulation
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / metabolism
  • Oligodendrocyte Transcription Factor 2
  • Oligodendroglia / cytology*
  • Oligodendroglia / metabolism
  • Rats
  • Spinal Cord / cytology
  • Transcription Factors / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Olig2 protein, mouse
  • Olig2 protein, rat
  • Oligodendrocyte Transcription Factor 2
  • Transcription Factors
  • Smarca4 protein, mouse
  • DNA Helicases

Associated data

  • GEO/GSE42454