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. 2021 Mar 9;12:1536. doi: 10.1038/s41467-021-21784-2

Fig. 2. A chemical screen identifies epigenetic modulators of phenotypic heterogeneity.

Fig. 2

a t-SNE maps comparing single-cell heterogeneity in differentiation state (Mitf, Ngfr, and Axl) and MAPK signaling (p-ErkT202/Y204, p-S6S235/S236, and Ki67) within two BRAFV600E melanoma cell lines, MMACSF and COLO858, following exposure to vehicle (DMSO), vemurafenib (at 100 nM), alone or in combination with trametinib (at 10 nM), for 72 and 120 h. b Log2-normalized changes in live cell count following exposure of COLO858 and MMACSF cells to either DMSO, vemurafenib (at 100 nM), or vemurafenib (at 100 nM) plus trametinib (at 10 nM), for a period of 120 h. Cells were pretreated for 24 h with either DMSO (top panels) or two different doses (0.2 and 1 μM) of each of the 276 epigenetic-modifying compounds (bottom panels). Data for treatments without epigenetic modifiers (top panels) are presented as mean values ± s.d. calculated across n = 276 biologically independent samples examined over 25 independent experiments. Data for treatments with epigenetic modifiers (bottom panels) are presented as the average of n = 2 biologically independent samples. c A schematic representation of the overall procedure of data collection, processing (normalization), integration, and hierarchical clustering using measurements of cellular grow rate, Mitf, p-RbS807/S811, and p-ErkT202/Y204 at indicated treatment conditions and timepoints in MMACSF and COLO858 cells. Unsupervised clustering analysis was performed on data collected for 58 epigenetic compounds that led to a statistically significant decrease in normalized growth rate (when used either as a single agent, or in combination with Braf/Mek inhibitors) in either or both cell lines. Prior to clustering, data collected for cells treated with each epigenetic compound and MAPK inhibitor condition (i.e., DMSO, vemurafenib, or vemurafenib plus trametinib) were normalized to cells treated without any epigenetic compound and the same MAPK inhibitor condition. Groups of compounds with similar nominal epigenetic targets are listed on the right side. Source data are provided as a Source data file.