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Epigenetic modulations rendering cell-to-cell variability and phenotypic metastability
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作者 Shawal Spencer Agustina Gugliotta +2 位作者 Natascha Godecke Hansjorg Hauser Dagmar Wirth 《Journal of Genetics and Genomics》 SCIE CAS CSCD 2016年第8期503-511,共9页
Tumor cells display phenotypic plasticity and heterogeneity due to genetic and epigenetic variations which limit the predictability of therapeutic interventions. Chromatin modifications can arise stochas- tically but ... Tumor cells display phenotypic plasticity and heterogeneity due to genetic and epigenetic variations which limit the predictability of therapeutic interventions. Chromatin modifications can arise stochas- tically 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 epige- netic 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 genorne. Single-cell analysis showed high intraclonal heterogeneity. Epige- netic 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. 展开更多
关键词 lntraclonal heterogeneityEpigenetic regulationdna methylationDifferential histone marksMetastable expression
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