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

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

Author information

1
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden.
2
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
3
National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
4
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden jonas.muhr@ki.se maria.bergsland@ki.se.

Abstract

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

PMID:
30166336
PMCID:
PMC6216240
[Available on 2019-11-01]
DOI:
10.15252/embr.201846635
[Indexed for MEDLINE]

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