Fig. 5: Long-range interactions.
a Top: whole-genome summary of CNV-mQTL/CpG pairs that overlap with interacting Hi-C regions. The size of each point corresponds to the Hi-C interaction signal, denoted by the KR normalization score (green, proximal CNV-mQTLs; orange, distal CNV-mQTLs). a Bottom: enrichment analysis. The bars show the frequency of permutated CNV-mQTL/CpG datasets overlapping with Hi-C compartments at 10 kb resolution; the blue fitted line shows the distribution of 1000 permutation sets; the red line denotes the number of actual CNV-mQTL/CpG pairs overlapping with Hi-C compartments (p < 0.001, permutation test). b Schematic of a potential mechanism by which CNV-mQTLs may influence distal CpG methylation. Ideogram shows three CNV-mQTLs (red boxed region) that are all associated with the methylation of the genes NKIRAS2 (proximal), WSB1 (distal), and PRKAR1A (distal). Box and whiskers plots show correlation between the mQTL and each of the three genes. NKIRAS2 inhibits the activation of the RELA subunit of the TF, NFκB. NFκB is known to regulate WSB1 methylation through its interaction with DNMT1. In a normal state, looping interactions between the CNV-mQTLs and the proximally associated gene NKIRAS2 could potentially activate its expression and inhibit NFκB activation, thereby decreasing methylation WSB1 and PRKAR1A. Conversely, a deletion in the CNV-mQTL region may lead to reduced NKIRAS2 expression and, thereby, increased methylation of the distally associated genes, WSB1 and PRKAR1A, mediated by activated NFκB.
