title: The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity.
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.
authors.affiliation: Cancer Epigenetics Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Cristina Morales
authors.initials: CM
authors.lastname: Torres
authors.affiliation: Department of Genetics, The Institute of Life Sciences, and The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 91904, Israel.
authors.forename: Alva
authors.initials: A
authors.lastname: Biran
authors.affiliation: Cancer Epigenetics Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Burney
authors.affiliation: Bioinformatics, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Harshil
authors.initials: H
authors.lastname: Patel
authors.affiliation: Cancer Epigenetics Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Tristan
authors.initials: T
authors.lastname: Henser-Brownhill
authors.affiliation: Department of Genetics, The Institute of Life Sciences, and The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 91904, Israel.
authors.forename: Ayelet-Hashahar Shapira
authors.initials: AS
authors.lastname: Cohen
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB101SA, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat-Gan, 52900, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Ben-Hamo
authors.affiliation: Experimental Histopathology, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.affiliation: Experimental Histopathology, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.affiliation: Bioinformatics, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat-Gan, 52900, Israel.
authors.forename: Sol
authors.initials: S
authors.lastname: Efroni
authors.affiliation: Advanced sequencing, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.affiliation: National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
authors.affiliation: Department of Genetics, The Institute of Life Sciences, and The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, 91904, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Meshorer
authors.affiliation: Cancer Epigenetics Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, London WC2A 3LY, UK.|UCL Cancer Institute, University College London, London WC1E 6DD, UK.
authors.forename: Paola
authors.initials: P
authors.lastname: Scaffidi
mesh_terms: D000225:Adenine / Q000737:chemistry; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018740:Genetic Heterogeneity; D006657:Histones / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D009707:Nucleosomes / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013941:Thymine / Q000737:chemistry
chemical_list: D006657:Histones; D009707:Nucleosomes; D034741:RNA, Small Interfering; D004247:DNA; D000225:Adenine; D013941:Thymine