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.
Bibliographical noteFunding 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.
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