Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance

Cell Stem Cell. 2019 Mar 7;24(3):462-476.e6. doi: 10.1016/j.stem.2019.02.004.

Abstract

The SOX2 transcription factor is critical for neural stem cell (NSC) maintenance and brain development. Through chromatin immunoprecipitation (ChIP) and chromatin interaction analysis (ChIA-PET), we determined genome-wide SOX2-bound regions and Pol II-mediated long-range chromatin interactions in brain-derived NSCs. SOX2-bound DNA was highly enriched in distal chromatin regions interacting with promoters and carrying epigenetic enhancer marks. Sox2 deletion caused widespread reduction of Pol II-mediated long-range interactions and decreased gene expression. Genes showing reduced expression in Sox2-deleted cells were significantly enriched in interactions between promoters and SOX2-bound distal enhancers. Expression of one such gene, Suppressor of Cytokine Signaling 3 (Socs3), rescued the self-renewal defect of Sox2-ablated NSCs. Our work identifies SOX2 as a major regulator of gene expression through connections to the enhancer network in NSCs. Through the definition of such a connectivity network, our study shows the way to the identification of genes and enhancers involved in NSC maintenance and neurodevelopmental disorders.

Keywords: ChIA-PET; SOX2; chromatin connectivity; neural stem cells; transcription factors.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Chromatin / metabolism*
  • Gene Regulatory Networks / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Neural Stem Cells / metabolism*
  • SOXB1 Transcription Factors / deficiency
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism*
  • Zebrafish

Substances

  • Chromatin
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse