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Fig. 5 | Genome Biology

Fig. 5

From: MICMIC: identification of DNA methylation of distal regulatory regions with causal effects on tumorigenesis

Fig. 5

Interplay between distal DRE methylation and the cognate transcription factor binding has profound effects on tumorigenesis. Bar charts show the enriched transcription factors (TFs) that bind to DREs showing a negative correlation between the average methylation of TF binding motifs and TF expression, with (a) downregulation (negative-down DREs) or (b) upregulation (negative-up DREs) of the target gene. Intensity of blue color indicates the degree of tissue specificity of the TF in breast cancer (BRCA) compared to other tissue types. Intensity of red/green color indicates the degree of oncogenic/tumor suppressive behavior of the TF. Bar chart showing the enriched TFs binding on the group-specific distal DREs. The TFs were ranked by the negative correlation between the TF expression and average DNA methylation of the TF binding motifs on the group-specific distal DREs. The correlation value is shown on the y-axis. Colors represent the tissue type significance or master regulator significance of the TF gene. The cancer signature association of the TFs is shown in the inset GSEA plot. c Representative examples of TFs that showed a negative correlation between the expression of the TF and average DNA methylation of the TF binding motifs on distal DREs. d Heatmap showing the enrichment significance of DREs associated with patient survival in various genomic regions. The heatmap color and number indicates the enrichment p value of DREs associated with patient survival in each category. e Higher impact of distal DREs on cancer genes compared with promoter DREs during initiation (top) and progression (bottom). Y-axis for the two top waterfall plots indicates the master regulator significance for each gene, ranked from tumor-suppressive to oncogenic. Y-axis for the two bottom panels shows the density of normalized gene counts controlled by promoter or distal DREs. See results of other cancers in Additional file 1: Figure S16. f Heatmap showing the enrichment significance of distal DREs associated with patient survival in the four methylation patterns of distal DREs, i.e. “consistent,” “reversed,” “stronger,” and “weaker” according to the direction of methylation change from the initiation to progression stage of tumorigenesis for each cancer type. The number in each square represents the p values. g Example of two distal-DRE target pairs identified in uterine cancer that show a “reversed” methylation pattern. Box plots on the x-axis show the DRE is demethylated during the initiation stage but becomes remethylated during cancer progression. High methylation of both DREs and low expression of their target genes were associated with poorer patient survival

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