Mapping the global chromatin connectivity network for Sox2 function in neural stem cell maintenance

Journal Article: Cell Stem CellYear Published: (2019) Volume Number: 24, Article Number: 462-476 e6

Authors

Bertolini, Jessica A.; Favaro, Rebecca; Zhu, Yanfen; Pagin, Miriam; Ngan, Chew Yee; Wong, Chee Hong; Tjong, Harianto; Vermunt, Marit W.; Martynoga, Ben; Barone, Cristiana; Mariani, Jessica; Cardozo, Marcos Julián; Tabanera, Noemi; Zambelli, Federico; Mercurio, Sara; Ottolenghi, Sergio; Robson, Paul; Creyghton, Menno P.; Bovolenta, Paola; Pavesi, Giulio; Guillemot, Francois; Nicolis, Silvia K.; Wei, Chia-Lin

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.