title: Epigenetic modulations rendering cell-to-cell variability and phenotypic metastability.
abstract: Tumor cells display phenotypic plasticity and heterogeneity due to genetic and epigenetic variations which limit the predictability of therapeutic interventions. Chromatin modifications can arise stochastically but can also be a consequence of environmental influences such as the microenvironment of cancer cells. A better understanding of the impact and dynamics of epigenetic modulation at defined chromosomal sites is required to get access to the underlying mechanisms. We investigated the epigenetic modulations leading to cell-to-cell heterogeneity in a tumor cell line model. To this end, we analyzed expression variance in 80 genetically uniform cell populations having a single-copy reporter randomly integrated in the genome. Single-cell analysis showed high intraclonal heterogeneity. Epigenetic characterization revealed that expression heterogeneity was accompanied by differential histone marks whereas contribution of DNA methylation could be excluded. Strikingly, some clones revealed a highly dynamic, stochastically altered chromatin state of the transgene cassette which was accompanied with a metastable expression pattern. In contrast, other clones represented a robust chromatin state of the transgene cassette with a stable expression pattern. Together, these results elucidate locus-specific epigenetic modulation in gene expression that contributes to phenotypic heterogeneity of cells and might account for cellular plasticity.
authors: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
authors: Shawal
authors: S
authors: Spencer
authors: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
authors: Agustina
authors: A
authors: Gugliotta
authors: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
authors: Natascha
authors: N
authors: Gödecke
authors: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany.
authors: Hansjörg
authors: H
authors: Hauser
authors: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig 38124, Germany; Experimental Hematology, Hannover Medical School, Hannover 30625, Germany. Electronic address: dagmar.wirth@helmholtz-hzi.de.
authors: Dagmar
authors: D
authors: Wirth
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D009362:Neoplasm Metastasis / Q000235:genetics*; D010641:Phenotype; D013269:Stochastic Processes
chemical_list: D002843:Chromatin; D006657:Histones
keywords: DNA methylation; Differential histone marks; Epigenetic regulation; Intraclonal heterogeneity; Metastable expression