Profiling non-CG DNA methylation levels throughout the 22 ADS-iPSC hypomethylated mega-DMRs for each ES cell and iPSC line, we found that depletion of non-CG methylation was a common feature of the independent iPSC lines (Fig. 5b, Supplementary Figs 1b, 17 and Supplementary Table 4). We proposed that the localized failure to restore non-CG methylation in these large regions could be mechanistically linked to the presence of particular covalent histone modifications that impart a regional chromatin conformation that is refractive to remethylation at CH sites during reprogramming. Indeed, we identified significant regional enrichment of trimethylation of histone H3 lysine 9 (H3K9me3) in two iPSC lines25 that was spatially concordant with the non-CG mega-DMRs, and absent in H1 ES cells (Fig. 5c). The IMR90 genome also showed enrichment of H3K9me3 highly spatially correlated with the non-CG mega-DMRs. Additionally, we found that the non-CG mega-DMRs tend to be partially methylated in the CG context in non-pluripotent cells (99.5% of non-CG mega-DMR bases are partially methylated in ADS cells; Fig. 5d). Taken together, these data indicate that specific large regions of somatic cell genomes
