The Open Targets Cell Line Epigenome Project: Determining the Biological Relevance of Cellular Assay Models through Epigenetic Analysis
Recorded On: 02/07/2018
The Open Targets Cell Line Epigenome Project addresses the challenge of selecting appropriate cellular models for target validation and drug screening that exhibit sufficient relevance to pathways and phenotypes associated with a particular disease or biology. The implementation of more complex, disease relevant models through use of 3D culture, tissue slices and primary cells is improving the predictive power of in vitro assays. However, due to limitations in cell and tissue supply, scalability, assay reproducibility and amenability to genetic manipulation, there often remains a need to utilise transformed cell lines, particularly for higher throughput cellular screens and gene editing studies. Currently cell lines are often chosen for these purposes based on historical usage, even if they are a poor substitute for that cell type or tissue. To address the gap in data driven cell line and model selection, we have developed a novel systematic approach to determine biological relevance through the generation and analysis of transcriptomic and epigenomic data. Epigenomic and transcriptomic profiles (RNA/ChIP/ATAC-seq) from common immortalised cell models have been generated and integrated with publicly available reference data from primary cells. Statistical methods have been developed to score cells based on distance / similarity at the global genome level or more specific gene sets, signaling pathways or genomic loci of interest. The data and tools we have generated provide an impactful framework enabling biologists to select the most appropriate, predictive cellular model for their research and to better establish optimal assay critical paths for translating target biology & compound pharmacology to the clinic. In this presentation we will demonstrate how we have used this approach to quantify the impact of 2D vs. 3D culture in cellular models of liver drug toxicity; identify the most relevant immune cell models of inflammatory response and validate immortalised cell surrogates for genome wide gene editing studies.
Screening Profiling & Mechanistic Biology, GlaxoSmithKline
Following a PhD at Imperial College London focusing on expression of P-glycoprotein and the development of multidrug resistance in cancer, I established a career in the pharmaceutical industry with positions at UCB-Celltech (Cambridge, UK) and GlaxoSmithKine (Stevenage, UK). I have a strong background in cell biology, phenotypic screening and a deep interest in epigenetics. I currently work within GSK’s Screening Profiling and Mechanistic Biology Department (within Platform Technology and Science) as a cell biologist and program leader. My role involves leadership of GSK early drug discovery programs and external collaborative projects such as the Cell Line Epigenome Project, an Open Targets project in collaboration with EMBL-EBI and the Wellcome Trust Sanger Institute.