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  • EMBO reports: 19 (11)

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

View ORCID ProfileSusanne Klum, View ORCID ProfileCécile Zaouter, View ORCID ProfileZhanna Alekseenko, View ORCID ProfileÅsa K Björklund, Daniel W Hagey, Johan Ericson, View ORCID ProfileJonas Muhr, View ORCID ProfileMaria Bergsland
DOI 10.15252/embr.201846635 | Published online 30.08.2018
EMBO reports (2018) 19, e46635
Susanne Klum
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Cécile Zaouter
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Zhanna Alekseenko
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Åsa K Björklund
National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
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Daniel W Hagey
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Johan Ericson
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Jonas Muhr
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Maria Bergsland
Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, SwedenDepartment of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Author Affiliations

  1. Susanne Klum1,2,†,
  2. Cécile Zaouter1,2,†,
  3. Zhanna Alekseenko2,
  4. Åsa K Björklund3,
  5. Daniel W Hagey1,2,
  6. Johan Ericson2,
  7. Jonas Muhr (jonas.muhr{at}ki.se)*,1,2 and
  8. Maria Bergsland (maria.bergsland{at}ki.se)*,1,2
  1. 1Ludwig Institute for Cancer Research, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
  3. 3National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  1. ↵* Corresponding author. Tel: +46 7068 05017; E‐mail: jonas.muhr{at}ki.se
    Corresponding author. Tel: +46 7365 36361; E‐mail: maria.bergsland{at}ki.se
  1. ↵† These authors contributed equally to this work

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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.

Synopsis

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By single‐cell RNA‐seq and ChIP‐seq analyses this study defines gene expression in spinal cord gliogenesis and reveals how sequentially expressed SOX proteins control glial gene expression in a temporal and sub‐lineage specific fashion.

  • Astrocyte‐ and oligodendrocyte‐specific gene expression is defined in the developing mouse spinal cord.

  • SOX3 and SOX9 preselect gene programs in NPCs and GPCs that are first activated during gliogenesis.

  • Temporal onset of astrocyte gene expression is coordinated by SOX3‐mediated repression of SOX9 activation.

  • ChIP‐seq
  • gliogenesis
  • prebinding
  • single‐cell RNA‐sequencing
  • SOX proteins

EMBO Reports (2018) 19: e46635

  • Received June 25, 2018.
  • Revision received July 24, 2018.
  • Accepted August 7, 2018.
  • © 2018 The Authors
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Volume 19, Issue 11
01 November 2018
EMBO reports: 19 (11)
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