Extended Data Fig. 1: Epigenomic characterization of GIST.

a, ChIP–seq profiles for H3K27ac were compared for GIST specimens and other gastrointestinal tract tumour specimens (GAC, gastric adenocarcinoma; CRC, colorectal cancer; PDAC, pancreatic ductal adenocarcinoma). Heat map depicts pairwise Pearson correlations between the top 10,000 most variable peaks (yellow indicates high correlation; blue indicates low correlation). The dendrogram (left) was derived by unweighted average distance linkage. Enhancer patterns are relatively consistent across GIST subtypes, compared to other tumour types. b, DNA methylation levels in the vicinity of CTCF sites were profiled genome-wide by hybrid-selection bisulfite sequencing. CTCF sites are binned according to the amount their methylation increased in SDH-deficient GISTs, relative to SDH-intact GISTs (methylation change computed over a 250 bp window centred on the motif). For each bin, bar graphs depict the percentage of sites that lose CTCF binding in SDH-deficient GISTs, per ChIP–seq. Separate plots are shown for CTCF sites for which motifs do or do not contain a CpG. Increased methylation over CTCF sites is associated with more frequent loss of CTCF binding, even when the CTCF motif lacks a CpG. c, Plot depicts correlation between CTCF occupancy and DNA methylation in SDH-deficient GISTs. Red points show Spearman correlations between CTCF ChIP–seq signal and methylation of CpGs at indicated positions relative to the centre of the CTCF motif. Red line reflects correlation to average methylation over 10 bp windows. Randomly permuted data (black) are shown for comparison. Anti-correlation between CTCF occupancy and methylation is evident over a ~250-bp binding footprint. d, Genomic views of a representative 10 Mb region on chromosome 21 depict chromosome topology (HiC, red), CTCF binding (ChIP–seq, orange) and CTCF–CTCF loop interactions (HiChIP, black) for the SDH-intact GIST model, GIST-T1. TADs are visible as triangles of enhanced interaction in HiC data, flanked by boundaries that correspond to loop interactions in HiChIP data. Genes (blue) are also indicated.