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


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.