Sequentially acting SOX proteins orchestrate astrocyte- and oligodendrocyte-specific gene expression

EMBO Rep. 2018 Nov;19(11):e46635. doi: 10.15252/embr.201846635. Epub 2018 Aug 30.


SOX transcription factors have important roles during astrocyte and oligodendrocyte development, but how glial genes are specified and activated in a sub-lineage-specific fashion remains unknown. Here, we define glial-specific gene expression in the developing spinal cord using single-cell RNA-sequencing. Moreover, by ChIP-seq analyses we show that these glial gene sets are extensively preselected already in multipotent neural precursor cells through prebinding by SOX3. In the subsequent lineage-restricted glial precursor cells, astrocyte genes become additionally targeted by SOX9 at DNA regions strongly enriched for Nfi binding motifs. Oligodendrocyte genes instead are prebound by SOX9 only, at sites which during oligodendrocyte maturation are targeted by SOX10. Interestingly, reporter gene assays and functional studies in the spinal cord reveal that SOX3 binding represses the synergistic activation of astrocyte genes by SOX9 and NFIA, whereas oligodendrocyte genes are activated in a combinatorial manner by SOX9 and SOX10. These genome-wide studies demonstrate how sequentially expressed SOX proteins act on lineage-specific regulatory DNA elements to coordinate glial gene expression both in a temporal and in a sub-lineage-specific fashion.

Keywords: ChIP‐seq; SOX proteins; gliogenesis; prebinding; single‐cell RNA‐sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / physiology*
  • Cell Differentiation / genetics
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Developmental
  • Mice
  • Neural Stem Cells
  • Neuroglia / cytology
  • Neuroglia / physiology
  • Oligodendroglia / physiology*
  • SOX9 Transcription Factor / genetics*
  • SOX9 Transcription Factor / metabolism
  • SOXB1 Transcription Factors / genetics*
  • SOXB1 Transcription Factors / metabolism
  • Spinal Cord / cytology*
  • Spinal Cord / growth & development


  • SOX9 Transcription Factor
  • SOXB1 Transcription Factors
  • Sox3 protein, mouse
  • Sox9 protein, mouse