Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewal

Genome Res. 2015 Jan;25(1):41-56. doi: 10.1101/gr.173435.114. Epub 2014 Oct 7.

Abstract

The gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation
  • Cells, Cultured
  • Cluster Analysis
  • Epigenomics
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks*
  • Logistic Models
  • Mice
  • Microarray Analysis
  • Models, Theoretical
  • NFI Transcription Factors / genetics
  • NFI Transcription Factors / metabolism
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Stem Cells / cytology*
  • Oligodendrocyte Transcription Factor 2
  • Regulatory Sequences, Nucleic Acid
  • SOX Transcription Factors / genetics
  • SOX Transcription Factors / metabolism
  • Sequence Analysis, DNA

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • NFI Transcription Factors
  • Nerve Tissue Proteins
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • SOX Transcription Factors