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

Summary

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.

Graphical Abstract

Highlights

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  Sox2-bound enhancers are enriched within long-range interactions in neural stem cells

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  SOX2 loss decreases chromatin interactivity genome-wide

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  Sox2-bound enhancers from interactions activate reporter genes in zebrafish forebrain

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  Socs3, a gene downregulated in Sox2 mutant NSCs, rescues their self-renewal

Abstract

Bertolini et al. report that long-range chromatin interactions in neural stem cells (NSCs) are enriched in Sox2-bound enhancers; in Sox2-deleted NSCs, interactions are reduced. Genes downregulated in Sox2-deleted cells are enriched in interactions with enhancers normally Sox2-bound. Overexpression of Socs3, a gene downregulated in mutant NSCs, rescues long-term NSC self-renewal.