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.

Highlights

  • Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential

  • We have shown by gene expression analysis that self-renewing tumor cells, which are marked by the surface antigen SSEA1 (SSEA1+ cells), are molecularly distinct from their SSEA1- differentiated progeny (Fig. S1A) [15]

  • Cell-to-cell signaling such as Wnt, Tgfβ and Notch pathways, have been shown to play critical roles in driving functional heterogeneity within tumors [38], but very little is known about the downstream, cell-intrinsic mechanisms that translate signaling into differential cell function

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Summary

Introduction

Tumors comprise functionally diverse subpopulations of cells with distinct proliferative potential. Phenotypic and functional heterogeneity can be mapped to distinct differentiation states [5,6,7], suggesting that epigenetic changes occurring during tumor growth may establish cellular hierarchies within the neoplastic mass, thereby affecting the long-term proliferative potential of cancer cells. In line with this notion, individual tumors have been shown to contain distinct subpopulations of undifferentiated, self-renewing cells, and more differentiated cells, which only have limited proliferative ability [8, 9]. The functional differences that distinguish SSEA1+ and SSEA1- tumor cells – undifferentiated phenotype, long-term self-renewal ability and high tumorigenic potential versus differentiated phenotype, limited proliferative potential and low tumorigenicity - are general features associated with differentiation hierarchies in many cancer types, regardless of the tissue of origin

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