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Genetic screening for single-cell variability modulators driving therapy resistance

ABSTRACT: We present the transcriptome of WM989 melanona cells without or without inhibition of DOT1L. Different samples represent either the bulk population of melanoma cells, or subpopulations that express high or low levels of the drug resistance markers EGFR and NGFR

ORGANISM(S): Homo sapiens

PROVIDER: GSE149280 | GEO | 2020/04/25

REPOSITORIES: GEO

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Genetic screening for single-cell variability modulators driving therapy resistance.

Project description:Cellular plasticity describes the ability of cells to transition from one set of phenotypes to another. In melanoma, transient fluctuations in the molecular state of tumor cells mark the formation of rare cells primed to survive BRAF inhibition and reprogram into a stably drug-resistant fate. However, the biological processes governing cellular priming remain unknown. We used CRISPR-Cas9 genetic screens to identify genes that affect cell fate decisions by altering cellular plasticity. We found that many factors can independently affect cellular priming and fate decisions. We discovered a new plasticity-based mode of increasing resistance to BRAF inhibition that pushes cells towards a more differentiated state. Manipulating cellular plasticity through inhibition of DOT1L before the addition of the BRAF inhibitor resulted in more therapy resistance than concurrent administration. Our results indicate that modulating cellular plasticity can alter cell fate decisions and may prove useful for treating drug resistance in other cancers.

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Genetic screening for single-cell variability modulators driving therapy resistance [WM989-A6-G3-Cas9 5a3]

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Genetic screening for single-cell variability modulators driving therapy resistance

Project description:Genetic screening for single-cell variability modulators driving therapy resistance

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Genetic screening for single-cell variability modulators driving therapy resistance [WM989-A6-G3-Cas9 5a3]

Project description:Genetic screening for single-cell variability modulators driving therapy resistance [WM989-A6-G3-Cas9 5a3]

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Gene expression profiles of normal human tonsillar cell subpopulations FACS sorted based on expression of cell surface markers

Project description:To characterize the progenitor-enriched CD44+NGFR+ cells present in the crypt and surface regions of the tonsil, we used an Illumina array system to analyze the transcriptome of these cells isolated from the tonsillar crypt and surface regions of three different individuals as well as the total epithelial (CD45-CD31-) populations obtained from two of these. To enrich for epithelial progeniors in human palatine tonsil tissue, hematopoietic and endothelial cells were depleted from freshly isolated cell suspensions derived from palatine tonsils using fluorescence-activated cell sorting (FACS). The resultant CD45-CD31- population was further fractionated into four subpopulations using antibodies against CD44 and NGFR. Based on the immunohistochemical phenotype and in vitro functional assays, CD44+NGFR+ subpopulations were identified as epithelial progenitor-enriched subsets. Microarray profiling was used to derive gene expression signatures of CD45-CD31- subsets (total epithelial-enriched) and CD45-CD31-CD44+NGFR+ subpopulations (progenitor-enriched).

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DOT1L complex regulates transcriptional initiation in human cells

Project description:DOT1L, the only H3K79 methyltransferase in human cells and a homolog of the yeast Dot1, normally forms a complex with AF10, AF17 and ENL/AF9, is dysregulated in most of the cases of mixed lineage leukemia (MLL) and is believed to regulate transcriptional elongation without much evidence. Here we show that the depletion of DOT1L reduced the global occupancy without affecting the traveling ratio or the elongation rate of Pol II, suggesting it not a major player in elongation. An examination of general transcription factors (GTFs) binding revealed globally reduced TBP and TFIIA occupancies near promoters after DOT1L loss, pointing to a role in transcriptional initiation. Proteomic studies uncovered that DOT1L regulates transcriptional initiation likely by facilitating the recruitment of TFIID. Moreover, we found that ENL also regulates transcriptional initiation and that DOT1L stimulates H2B monoubiquitination by limiting the recruitment of human SAGA complex. These results advanced current understanding of epigenetic regulation of transcriptional initiation and roles of DOT1L complex in MLL.

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