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Mapping the global chromatin connectivity network for Sox2 function in neural stem cell maintenance
journal contributionposted on 2019-12-11, 16:07 authored by Jessica A Bertolini, Rebecca Favaro, Yanfen Zhu, Miriam Pagin, Chew Yee Ngan, Chee Hong Wong, Harianto Tjong, Marit W Vermunt, Ben Martynoga, Cristiana Barone, Jessica Mariani, Marcos Julián Cardozo, Noemi Tabanera, Federico Zambelli, Sara Mercurio, Sergio Ottolenghi, Paul Robson, Menno P Creyghton, Paola Bovolenta, Giulio Pavesi, Francois Guillemot, Silvia K Nicolis, Chia-Lin Wei
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.