The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity

摘要: INTRODUCTION Cancer arises from clonal expansion of a single cell. Yet, most human cancers are characterized by extensive intratumor heterogeneity and comprise various subpopulations cells with distinct phenotypes biological properties. Intratumor poses major challenges in understanding cancers, managing patients, designing effective treatment strategies. Functional within individual tumors is partly due to the presence genetically subclonal cell populations. Furthermore, interactions between cancer tumor microenvironment can alter phenotype via nongenetic mechanisms. The combination cell-intrinsic cell-extrinsic changes occurring during growth generates functionally subsets that differentially contribute maintenance. RATIONALE In many phenotypic functional be mapped differentiation states, suggesting cellular hierarchies established may affect long-term proliferative potential cells. To shed light on mechanisms responsible for generation these hierarchies, we searched epigenetic determine which preserve unlimited potential, thus ability drive growth, lose this through process. RESULTS We found that, several types, exhibit high chromatin protein linker histone H1.0, showing strongly reduced H1.0 levels self-renewal tumorigenic higher nontumorigenic Combined analysis pan-cancer patient data sets experimental alteration H1F0 locus revealed heterogeneous expression patterns differential methylation an enhancer region dynamically modulates tumors. Using controlled system model heterogeneity, showed maintenance required silencing avoid loss capacity differentiation. Mechanistically, absence led destabilization nucleosome-DNA AT-rich genomic regions coordinated derepression large neighboring genes, resulting activation transcriptional programs support self-renewal. Gene induced were reversible, states restricting reestablished upon reexpression. multiple agreement observed inhibition patients expressing overall significantly worse outcome than levels. CONCLUSION has emerged as general feature cancer, but molecular features underlying diverse have been elusive. Our results uncover determinants tumor-maintaining identify integral component important regulator propose only insensitive extracellular cues, capable permanently act self-renewing such mechanism supports types cancer. suggest intervention aimed at restoring all enhance process naturally occurs beneficial therapeutic purposes.