Torres, CM; Biran, A; Burney, MJ; Patel, H; Henser-Brownhill, T; Cohen, A-HS; Li, Y; ... Scaffidi, P; + view all Torres, CM; Biran, A; Burney, MJ; Patel, H; Henser-Brownhill, T; Cohen, A-HS; Li, Y; Ben-Hamo, R; Nye, E; Spencer-Dene, B; Chakravarty, P; Efroni, S; Matthews, N; Misteli, T; Meshorer, E; Scaffidi, P; - view fewer (2016) The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science , 353 (6307) , Article aaf1644. 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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