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 Pavesi; Francois Guillemot; Silvia K Nicolis; Chia-Lin Wei

doi:10.1016/j.stem.2019.02.004

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

76 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 language	English
Pages (from-to)	462-476.e6
Journal	Cell Stem Cell
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2019.02.004
Publication status	Published - 07 Mar 2019

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Bertolini, J. A., Favaro, R., Zhu, Y., Pagin, M., Ngan, C. Y., Wong, C. H., Tjong, H., Vermunt, M. W., Martynoga, B., Barone, C., Mariani, J., Cardozo, M. J., Tabanera, N., Zambelli, F., Mercurio, S., Ottolenghi, S., Robson, P., Creyghton, M. P., Bovolenta, P., ... Wei, C.-L. (2019). Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance. Cell Stem Cell, 24(3), 462-476.e6. https://doi.org/10.1016/j.stem.2019.02.004

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title = "Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance",

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.",

author = "Bertolini, {Jessica A} and Rebecca Favaro and Yanfen Zhu and Miriam Pagin and Ngan, {Chew Yee} and Wong, {Chee Hong} and Harianto Tjong and Vermunt, {Marit W} and Ben Martynoga and Cristiana Barone and Jessica Mariani and Cardozo, {Marcos Juli{\'a}n} and Noemi Tabanera and Federico Zambelli and Sara Mercurio and Sergio Ottolenghi and Paul Robson and Creyghton, {Menno P} and Paola Bovolenta and Giulio Pavesi and Francois Guillemot and Nicolis, {Silvia K} and Chia-Lin Wei",

year = "2019",

month = mar,

day = "7",

doi = "10.1016/j.stem.2019.02.004",

language = "English",

volume = "24",

pages = "462--476.e6",

journal = "Cell Stem Cell",

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Bertolini, JA, Favaro, R, Zhu, Y, Pagin, M, Ngan, CY, Wong, CH, Tjong, H, Vermunt, MW, Martynoga, B, Barone, C, Mariani, J, Cardozo, MJ, Tabanera, N, Zambelli, F, Mercurio, S, Ottolenghi, S, Robson, P, Creyghton, MP, Bovolenta, P, Pavesi, G, Guillemot, F, Nicolis, SK & Wei, C-L 2019, 'Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance', Cell Stem Cell, vol. 24, no. 3, pp. 462-476.e6. https://doi.org/10.1016/j.stem.2019.02.004

TY - JOUR

T1 - Mapping the Global Chromatin Connectivity Network for Sox2 Function in Neural Stem Cell Maintenance

AU - Bertolini, Jessica A

AU - Favaro, Rebecca

AU - Zhu, Yanfen

AU - Pagin, Miriam

AU - Ngan, Chew Yee

AU - Wong, Chee Hong

AU - Tjong, Harianto

AU - Vermunt, Marit W

AU - Martynoga, Ben

AU - Barone, Cristiana

AU - Mariani, Jessica

AU - Cardozo, Marcos Julián

AU - Tabanera, Noemi

AU - Zambelli, Federico

AU - Mercurio, Sara

AU - Ottolenghi, Sergio

AU - Robson, Paul

AU - Creyghton, Menno P

AU - Bovolenta, Paola

AU - Pavesi, Giulio

AU - Guillemot, Francois

AU - Nicolis, Silvia K

AU - Wei, Chia-Lin

PY - 2019/3/7

Y1 - 2019/3/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.stem.2019.02.004

DO - 10.1016/j.stem.2019.02.004

M3 - Article

C2 - 30849367

SN - 1934-5909

VL - 24

SP - 462-476.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 3

ER -

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

Abstract

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