DNA methylation at CG islands proximal to gene promoters and transcriptional start sites is inhibitory to transcriptional activity22. To address whether highly methylated CG islands in differentiated cells can be demethylated during iPSC reprogramming, we analysed CG-DMRs between the ES cells and somatic cells (1% FDR, twofold enrichment) that overlapped with CG islands. Of 3,507 CG-DMRs coincident with CG islands (CGI-DMRs), 1,904 and 374 were hypermethylated in ES cells and somatic cells, respectively. Of the 374 CGI-DMRs hypermethylated in somatic cells, 94% were hypomethylated in the iPSCs and were similar to ES cells (Supplementary Fig. 8). Of the 1,904 CGI-DMRs hypermethylated in ES cells, 83% were hypermethylated, similar to ES cells, in the iPSCs (Supplementary Fig. 9). Together, these results indicate that CG islands in iPSCs are predominantly reprogrammed to an ES-cell-like state and, in particular, hypermethylated CG islands are not especially resistant to reprogramming.
