Extended Data Fig. 5: Tissue-specific DNA hypomethylation of the STR^mut allele.

a, Upper panel depicts selected CpG sites hypomethylated on the STR^mut haplotype in thyroid (compare Fig. 5a). The tissue-specific methylation profiles of the STR^wt allele were established by allele-specific amplification from bisulfite treated DNA from either thyroid tissue (from n = 10 individuals per CpG site), skin fibroblasts (n = 7) or leukocytes (n = 6), and the methylation status (%methylated; mean±SEM) of six CpG sites (m1, m3, m6, m7, m8, m9) quantified following digestion with methylation-sensitive restriction endonucleases. Three CpG sites (m7, m8, m9) close to the STR^wt sequence were hypomethylated in thyroid compared to fibroblasts and leukocytes suggesting their relevance for thyroid-specific expression under normal conditions. b, Tissue-specific relative methylation of STR^mut (vs STR^wt) in thyroid tissue (from n = 2 participants with RTSH), cultured fibroblasts (n = 3), and leukocytes (n = 4). On the chromosome harboring STR^mut, m7 and m8 appear to be hypomethylated in fibroblasts albeit to lesser degree than in thyroid. In contrast, for the m9 site, hypomethylation of STR^mut chromosomes appears to be restricted to thyroid. The latter site locates to a binding motif of C/EBPB and is hypermethylated in fibroblasts (both, STR^wt and STR^mut). These results could indicate that in fibroblasts, binding of a forkhead domain TF (other than FOXE1) at the STR region produces a limited increase in accessibility that does not extend to m9. In thyroid, FOXE1 produces more extensive accessibility followed by hypomethylation and binding of an additional TF, that is, C/EBPB.

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