Loss of Linker Histone H1.0 Marks Self-Renewing Tumor Subpopulations

Human tumors often exhibit high functional heterogeneity, with subpopulations of cells having distinct differentiation states and proliferative capacities. However, the epigenetic changes that contribute to this heterogeneity remain incompletely understood. Using a mouse model of hierarchically organized tumors generated by transformation of dermal fibroblasts, Morales Torres, Biran, and colleagues found that expression of the linker histone H1.0 (encoded by H1F0) was lower in self-renewing cells marked by the surface antigen SSEA1. This finding was confirmed in samples from patients with glioblastoma; H1.0 was consistently expressed at low levels in SSEA1⁺ cells but heterogeneously expressed in SSEA⁻ cells, and self-renewing glioblastoma cells expressed lower levels of H1F0 than cells grown in differentiating conditions. Heterogeneous H1.0 expression was also observed in a number of other tumor types. Consistent with these findings, H1F0, which is unmethylated and expressed at high levels in most adult tissues, was highly methylated in SSEA1⁺ cells and corresponded with reduced H1F0 expression. Moreover, data from multiple types from The Cancer Genome Atlas revealed that H1F0 mRNA expression was inversely correlated with enhancer methylation, and low expression of H1F0 was associated with a poor clinical outcome in patients with glioblastoma, breast cancer, melanoma, liver cancer, kidney cancer, and low-grade glioma. Overexpression of H1.0 induced differentiation and impaired the long-term proliferative capacity of tumor cells in vitro and in vivo, and, conversely, H1.0 depletion enhanced the self-renewal and proliferative potential of cancer cells. Mechanistically, H1.0 depletion preferentially destabilized nucleosome–DNA interactions in AT-rich regulatory elements to increase accessibility and derepress genes involved in cancer cell self-renewal. Collectively, these findings indicate an epigenetic mechanism by which H1.0 expression inhibits tumor maintenance by promoting differentiation, and suggests that strategies to restore H1.0 expression in tumor cells may have therapeutic potential by reducing the population of self-renewing cells.

Morales Torres C, Biran A, Burney MJ, Patel H, Henser-Brownhill T, Cohen AS, et al. The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 2016;353:aaf1644.

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