Epigenetic Modulations Rendering Cell-to-Cell Variability and Phenotypic Metastability

SPENCER, SHAWAL; GUGLIOTTA, AGUSTINA; GÖDECKE, NATASCHA; HAUSER, HANSJOERG; WIRTH, DAGMAR

JOURNAL OF GENETICS AND GENOMICS

SCIENCE PRESS

Lugar: Marrickville NSW; Año: 2016

1673-8527

Tumor cells display phenotypic plasticity and heterogeneity due to genetic and epigeneticvariations which limit the predictability of therapeutic interventions. Chromatinmodifications can arise stochastically but can also be a consequence of environmentalinfluences such as the microenvironment of cancer cells. A better understanding of theimpact and dynamics of epigenetic modulation at defined chromosomal sites is required toget access to the underlying mechanisms. We investigated the epigenetic modulations leadingto cell-to-cell heterogeneity in a tumor cell line model. To this end, we analyzed expressionvariance in 80 genetically uniform cell populations having a single-copy reporter randomlyintegrated in the genome. Single-cell analysis showed high intraclonal heterogeneity.Epigenetic characterization revealed that expression heterogeneity was accompanied bydifferential histone marks whereas contribution of DNA methylation could be excluded.Strikingly, some clones revealed a highly dynamic, stochastically altered chromatin state ofthe transgene cassette which was accompanied with a metastable expression pattern. Incontrast, other clones represented a robust chromatin state of the transgene cassette with astable expression pattern. Together, these results elucidate locus-specific epigeneticmodulation in gene expression that contributes to phenotypic heterogeneity of cells and mightaccount for cellular plasticity.