Fig. 6: Gene expression analysis unveils diverse roles of circadian genes in determining time-of-day patterns.

a Approach to identify the role of core clock genes in determining the strength of time-of-day (ToD) drug sensitivity. b Hierarchical clustering of Spearman rank correlation coefficients between drug-dependent ToD_MR-values (rows) and core clock genes (columns). Black boxes indicate examples shown in (c). Statistical significance of the correlations are indicated as stars, where * and **, denote p-values  ≤ 0.05 and 0.01, respectively. Exact p-values: Paclitaxel-Per3 = 0.002; Paclitaxel -Dbp = 0.030; Cisplatin-Dbp = 0.021; Torin2-Dbp = 0.036; 5-FU-Per2 = 0.050; Alpelisib-Bmal1 = 0.021; Alpelisib-Per2 = 0.047. Cisplatin and alpelisib: n = 8 cell lines, else n = 9 cell lines. c Example of linear correlation analysis between paclitaxel ToD_MR-values and Per3 or Dbp expression levels measured as log2(TPM). Color-coded data points indicate different cancer cell models. The gray continuous line indicates the normal distribution fit of the samples. Gray-shaded area = 95% CI of the linear regression fit. Model accuracy is indicated by R²-values. Top and lateral histograms indicate the count of samples along the range of gene expression, and ToD_MR-values, respectively. n = 9 cell lines. d Linear discriminant analysis (LDA) on median-based binarized ToD_MR-values for paclitaxel. Cell models with ToD_MR-values below or above the median (M) are colored in blue and red, respectively (middle and left panel). The contribution to the obtained discriminative information is shown in percentage for each of the circadian clock genes (right panel). e Boxplot showing the mean-based ranking of overall discriminative contributions of each circadian clock gene across all tested drugs. n = 8 drugs. Box bounds are defined by the 25^th and 75^th percentiles. Extending whiskers represent data points within 1.5 times the interquartile range from lower and upper quartiles. Red lines denote the data’s median, and white circles the mean. Source data for b–e are provided as a Source Data file.