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Cancer treatment and relapse : single-cell chromatin profiling of rare persister cells using droplet-based microfluidics

Abstract : The dynamic nature of chromatin and transcriptional features play a critical role in normal differentiation and are expected to contribute to tumor evolution. Studying the heterogeneity of chromatin alterations with single-cell resolution is mandatory to understand the contribution of epigenetic plasticity in cancer.In this thesis, I describe a droplet microfluidics approach to profile chromatin landscapes of thousands of cells at single-cell resolution, with an unprecedented coverage of 10,000 loci per cell.The system was evaluated to profile histone modifications associated with active (H3K4me3) and inactive transcription (H3K27me3) of human B cells and T cells, and revealed that >99% of the cells were correctly assigned to one cell type, defining distinct chromatin states of immune cells with high accuracy.In patient-derived xenograft (PDX) models of breast cancer with acquired drug resistance, the system enabled the detection of a rare subpopulation of cells in the untreated, drug-sensitive tumors with chromatin features characteristic of resistant cancer cells. These cells had lost chromatin marks (H3K27me3) associated with stable transcriptional repression for a number of genes known to promote resistance, potentially priming them for transcriptional activation.These results highlight the potential selection of cells with specific chromatin marks in response and in resistance to cancer therapy.
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Kevin Grosselin. Cancer treatment and relapse : single-cell chromatin profiling of rare persister cells using droplet-based microfluidics. Biochemistry, Molecular Biology. Université Paris sciences et lettres, 2018. English. ⟨NNT : 2018PSLET015⟩. ⟨tel-02981059⟩



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