Figure 9. Transcription factors become differentially active in a time-dependent cascade in TM.

The number of DATFs or SEGs at 3–24 hr are shown as bubbles. Blue, red, and white bubbles represent DATFs in T, M, and TM, respectively. TFs (gray bubbles) and SEGs (green bubbles) shown are ‘explained’ by the following mechanisms: double-down mechanism at the same (magenta arrow and number) or previous (angled magenta arrow) time point, the AND mechanism at the same (converging blue and red arrows and purple number) or previous (angled converging blue and red arrows) time point, or by connection to another TF ‘explained’ by one of these mechanisms at the same (see supplement 1), or previous (vertical arrows) time point. The total number and percentage of TFs or SEGs in TM meeting any of these criteria is shown. (See also Source data 10).

Figure 9—figure supplement 1. Cascade of differential transcription factor activity.

Connections between differentially active transcription factors in TM based on the MCF7 network. Each bubble represents a set of transcription factors that are differentially active in TM at a given timepoint. The codes on each bubble represent their differential activity status in Tamoxifen (first digit), Mefloquine, (second digit), and TM (third digit), where one is differentially active and 0 is not. Synergistic transcription factors in TM (001), are categorized into ‘explained’ bubbles (gray) or not explained (white). At each timepoint, synergistic transcription factors can be ‘explained’ by a network connection to a transcription factor that is differentially active in Tamoxifen and Mefloquine (111, magenta), or to at least one transcription factor in each of Tamoxifen alone (101, blue) and Mefloquine alone (011, red), or both, resulting in the left-hand, right-hand, and middle gray bubbles, respectively, in the middle layer. The fourth gray bubble in the lowest layer represents transcription factors which have connections to transcription factors in the middle ‘explained’ layer, but not to transcription factors in the top layer. Numbers in italics represent synergistic transcription factors that can be explained by connections to transcription factors that were active in monotherapies at the previous time point (blue, magenta, and red bubbled with dashed outlines at top of each timepoint). At the right in each time point, the dashed-outline bubble represents ‘explained’ transcription factors in the gray bubbles at the previous time point. Synergistic transcription factors not explained by other means which have a connection to any ‘explained’ transcription factors at the previous time point are shown in the gray bubble below the dashed-outline bubble. Finally, synergistic transcription factors that cannot be explained by any network connections are shown in the white bubble resulting from the ‘null’ set at each timepoint. The colors in this figure correspond to Figure 9, and the sum of all gray bubbles at each timepoint in this figure correspond to the single gray bubble shown at each timepoint in Figure 9. (See also Source data 10).