GSE110894 Enhancer remodeling overcomes therapeutic resistance driven by epigenetic evolution in cancer [single cell RNA-seq]

Contributors : Mark A Dawson ; Charles C Bell ; Enid Y LamSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusThe prevailing model of therapeutic resistance in cancer posits that malignant cells acquire genetic mutations in the context of therapeutic pressure that negate the efficacy of the drug. This mutation centric view of therapeutic resistance has recently been challenged by emerging evidence that shows a paucity of genetic diversity in malignant cells that evade therapeutic challenge emphasizing the role of epigenetic evolution in drug resistance. We have previously established that therapeutic resistance emerges in the absence of genetic adaptation from leukemia stem cells and whilst the clinical relevance of these findings has been established, what remains unanswered is whether transcriptional programs that confer resistance to therapies are pre-existing or acquired. It is also unclear how stable this adaptive transcriptional response is and whether it can be reversed. Here, we utilize a unique leukaemia model to highlight the key principles of epigenetic resistance. Using single cell RNA-seq with indexed flow sorting, we demonstrate that a form of Lamarckian evolution, namely transcriptional plasticity, drives epigenetic resistance. With a CRISPR-Cas9 screen we identify reciprocal regulators of the enhancer modification H3K4me1/2, LSD1 and MLL4, as important modulators of the resistant cell state. Knockdown or catalytic inhibition ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research