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Abstract
Steroid hormone receptors such as the Glucocorticoid Receptor (GR) mediate transcriptional responses to hormones and are frequently targeted in the treatment of human diseases. Experiments using bulk populations of cells have provided a detailed picture of the global transcriptional hormone response but are unable to interrogate cell-to-cell transcriptional heterogeneity. To examine the glucocorticoid response in individual cells, we performed single cell RNA sequencing (scRNAseq) in a human breast cancer cell line. The transcriptional response to hormone was robustly detected in individual cells and scRNAseq provided additional statistical power to identify over 100 GR-regulated genes that were not detected in bulk RNAseq. scRNAseq revealed striking cell-to-cell variability in the hormone response. On average, individual hormone-treated cells showed a response at only 30% of the total set of GR target genes. Understanding the basis of this heterogeneity will be critical for the development of more precise models of steroid hormone signaling.
Highlights
Steroid hormone receptors such as the Glucocorticoid Receptor (GR) mediate transcriptional responses to hormones and are frequently targeted in the treatment of human diseases
Cell-to-cell variability is observed in the transcriptomic profiles of individual cells within each of the 39 cell types observed in the mouse retina[1]
The scRNAseq was biased toward the detection of highly expressed genes, such that when we distributed the genes detected in the bulk RNAseq dataset into quintiles based on their expression levels, most genes in the top quintile and >80% of the genes in the second quintile were detected in the scRNAseq (Fig. 1d)
Summary
Steroid hormone receptors such as the Glucocorticoid Receptor (GR) mediate transcriptional responses to hormones and are frequently targeted in the treatment of human diseases. ScRNAseq revealed 39 transcriptionally distinct cell populations within the mouse retina[1], demonstrating the cellular and transcriptional complexity of multicellular life. Beyond the varied transcriptional profiles and patterns of hormone receptor expression that are observed within individual cell types or tumors, experiments performed with reporter genes have suggested that there is heterogeneity in the cellular response to hormone. In clonal populations of mouse Ltk-cells harboring low copy numbers of an MMTV-driven LacZ reporter, induction of LacZ expression by the synthetic glucocorticoid dexamethasone (Dex) was dose-dependent and significant heterogeneity was observed between cells within individual colonies[10]. While a response was detected in every Dex-treated cell, individual cells on average showed a response at only 30% of detected GRregulated genes Taken together, these data demonstrate that the transcriptional response to hormone is highly variable in individual cells
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