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

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 PavesiFrancois Guillemot, Silvia K Nicolis, Chia-Lin Wei

Research output: Contribution to journal/periodicalArticleScientificpeer-review

58 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)462-476.e6
JournalCell Stem Cell
Volume24
Issue number3
DOIs
Publication statusPublished - 07 Mar 2019

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