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Fig. 2 | Genome Biology

Fig. 2

From: Inferring regulatory element landscapes and transcription factor networks from cancer methylomes

Fig. 2

Linking differentially methylated probes to expression of nearby genes. a Shown is an illustration of the method used to associate each differentially methylated enhancer probe with one or more genes based on gene expression (see Methods section for additional details). For each of n probes identified as hypomethylated in a given cancer type (shown as blue circles), 10 genes upstream and 10 genes downstream were considered, yielding 20n statistical tests, one for each probe-gene pair. Each statistical test is performed across the complete set of normal and tumor samples within a particular cancer type. For instance, we show a scatterplot to illustrate such a test across the 258 endometrial (UCEC) tumor samples and 10 UCEC adjacent normals, showing the desired inverse correlation between methylation (x axis) and expression of the nearby gene (y axis). A Mann-Whitney U test was then performed, with the null hypothesis that the gene expression of group M samples is less or equal to that of group U samples. The U group consists of the 20 % least methylated samples for probe Pi, and the M group consists of the top 20 % most methylated. The raw P value (p r ) was compared to a permutation-based distribution of null P values, generated by performing 10,000 U tests between the actual gene Gj and DNA methylation a randomly selected distal non-enhancer probe. The empirical p e value was calculated by the rank of p r within the 10,000 trials. b Each scatter plot shows the methylation level of an example probe cg09606832 in all UCEC samples plotted against the expression of one of 20 adjacent genes. Only one gene, TFAP2A, shows a significant p e indicating negative correlation, and is considered the linked gene

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