Fig. 4
Genetic variation in nearby contextual sequences regulates GATA1 binding. a TFs whose motifs significantly alter GATA1 binding (% impact, median ± 95% CI) when disrupted by a discSNP. Vertical line indicates no effect, color indicates significance level. b DiscSNPs that directly disrupt a GATA motif have variable impacts on GATA1 binding depending on the number of positive co-regulatory motifs (from a) found within 100 bp of the discSNP. Wilcoxon's *p = 0.02, **p < 0.0004. Boxplot center is median, hinges are 25 and 75% percentiles. c Receiver operating characteristic curve (ROC) curves comparing logistic regression models that predict GATA1 binding based on either the GATA1 motif alone (PWM only), a combination of the GATA1 motif and nearby contextual regulatory motifs (contextual), or a control combination of the GATA1 motif and scrambled versions of the contextual motifs (shuffled). ROC curves are shown as median of 10 cross-validation runs. Area under the curve (AUC) is represented in the sub-panel as a boxplot of the 10 cross-validation runs, DeLong’s paired test for two correlated ROC curves: *p = 9e−13. Boxplot center is median, hinges are 25 and 75% percentiles, whisker is no >1.5*IQR. d Median ChIP-seq intensity of three TFs at their corresponding motifs in either an intact state or disrupted by a discSNP within a GATA1 peak. Position is shown relative to the discSNP position (400 bp upstream to 400 bp downstream). Significant differential binding (*) was assessed by a BH-corrected t test in the −200 to +200 region (TAL1: q = 0.008, ELF1: q = 0.008, TCF12: q = 0.25). e Sliding bins (10-bp wide, overlapping by 5 bp) test the impact of contextual motif disruption on proximal GATA1 binding as a function of relative distance to the nearest GATA1 motif. Colors represent significance in altering binding, permutation-adjusted for multiple hypothesis testing. f Sliding window medians of the impact of NFE2L2 and TAL1 motif disruption on GATA1 binding as a function of distance to motif. g Sliding window medians of the impact of GATA1 motif disruption on TAL1 binding as a function of distance to the nearest TAL1 motif
