The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

Cristina Morales Torres; Alva Biran; Matthew J. Burney; Harshil Patel; Tristan Henser-Brownhill; Ayelet Hashahar Shapira Cohen; Yilong Li; Rotem Ben-Hamo; Emma Nye; Bradley Spencer-Dene; Probir Chakravarty; Sol Efroni; Nik Matthews; Tom Misteli; Eran Meshorer; Paola Scaffidi

doi:10.1126/science.aaf1644

The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

Cristina Morales Torres, Alva Biran, Matthew J. Burney, Harshil Patel, Tristan Henser-Brownhill, Ayelet Hashahar Shapira Cohen, Yilong Li, Rotem Ben-Hamo, Emma Nye, Bradley Spencer-Dene, Probir Chakravarty, Sol Efroni, Nik Matthews, Tom Misteli, Eran Meshorer, Paola Scaffidi

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

115 Scopus citations

Abstract

Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells' long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells.

Original language	English
Article number	aaf1644
Journal	Science
Volume	353
Issue number	6307
DOIs	https://doi.org/10.1126/science.aaf1644
State	Published - 30 Sep 2016

Bibliographical note

Funding Information:
We thank M. Salton and D. Donato for assistance; D. Bonnet and M. Bustin for sharing mice and reagents; I. Malanchi for help with transplantation assays; M. Becker, P. Van Loo, and I. Varela for useful discussions; and the Crick core facilities for technical support. pdCas9-DNMT3A-EGFP and pdCas9-DNMT3A-EGFP (ANV) plasmids are available from Addgene under a material transfer agreement with V. Zoldos. The results published here are in part based upon data generated by The Cancer Genome Atlas pilot project established by the National Cancer Institute and the National Human Genome Research Institute. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001152), the UK Medical Research Council (FC001152), and the Wellcome Trust (FC001152), the Intramural Research Program of the NIH, NCI, Center for Cancer Research, the Israel Science Foundation (ISF 1252/12, 657/12), and the European Research Council (ERC-281781). Accompanying data sets are available through GEO (GSE65520, GSE66169, GSE73600, and GSE73580). Author contributions are in the supplementary text.

Publisher Copyright:
© 2016, American Association for the Advancement of Science. All rights reserved.

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https://science.sciencemag.org/content/sci/353/6307/aaf1644.full.pdf

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Torres, C. M., Biran, A., Burney, M. J., Patel, H., Henser-Brownhill, T., Cohen, A. H. S., Li, Y., Ben-Hamo, R., Nye, E., Spencer-Dene, B., Chakravarty, P., Efroni, S., Matthews, N., Misteli, T., Meshorer, E., & Scaffidi, P. (2016). The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science, 353(6307), Article aaf1644. https://doi.org/10.1126/science.aaf1644

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abstract = "Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Here, we show that dynamic epigenetic states defined by the linker histone H1.0 determine which cells within a tumor can sustain the long-term cancer growth. Numerous cancer types exhibit high inter- and intratumor heterogeneity of H1.0, with H1.0 levels correlating with tumor differentiation status, patient survival, and, at the single-cell level, cancer stem cell markers. Silencing of H1.0 promotes maintenance of self-renewing cells by inducing derepression of megabase-sized gene domains harboring downstream effectors of oncogenic pathways. Self-renewing epigenetic states are not stable, and reexpression of H1.0 in subsets of tumor cells establishes transcriptional programs that restrict cancer cells' long-term proliferative potential and drive their differentiation. Our results uncover epigenetic determinants of tumor-maintaining cells.",

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Torres, CM, Biran, A, Burney, MJ, Patel, H, Henser-Brownhill, T, Cohen, AHS, Li, Y, Ben-Hamo, R, Nye, E, Spencer-Dene, B, Chakravarty, P, Efroni, S, Matthews, N, Misteli, T, Meshorer, E & Scaffidi, P 2016, 'The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity', Science, vol. 353, no. 6307, aaf1644. https://doi.org/10.1126/science.aaf1644

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AU - Spencer-Dene, Bradley

AU - Chakravarty, Probir

AU - Efroni, Sol

AU - Matthews, Nik

AU - Misteli, Tom

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The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

Abstract

Bibliographical note

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