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Abstract  Haploinsufficiency of NSD1, which dimethylates histone H3 lysine 36 (H3K36), causes Sotos syndrome (SoS), an overgrowth syndrome. DNMT3A and DNMT3B recognizes H3K36 trimethylation (H3K36me3) through PWWP domain to exert de novo DNA methyltransferase activity and establish imprinted differentially methylated regions (DMRs). Since decrease of H3K36me3 and genome‐wide DNA hypomethylation in SoS were observed, hypomethylation of imprinted DMRs in SoS was suggested. We explored DNA methylation status of 28 imprinted DMRs in 31 SoS patients with  NSD1  defect and found that hypomethylation of  IGF2 ‐DMR0 and IG‐DMR in a substantial proportion of SoS patients. Luciferase assay revealed that  IGF2 ‐DMR0 enhanced transcription from the  IGF2  P0 promoter but not the P3 and P4 promoters. Chromatin immunoprecipitation‐quantitative PCR (ChIP‐qPCR) revealed active enhancer histone modifications at  IGF2 ‐DMR0, with high enrichment of H3K4me1 and H3 lysine 27 acetylation (H3K27ac). CRISPR‐Cas9 epigenome editing revealed that specifically induced hypomethylation at  IGF2 ‐DMR0 increased transcription from the P0 promoter but not the P3 and P4 promoters. NSD1 knockdown suggested that NSD1 targeted  IGF2 ‐DMR0; however,  IGF2 ‐DMR0 DNA methylation and  IGF2  expression were unaltered. This study could elucidate the function of  IGF2 ‐DMR0 as a DNA methylation dependent, P0 promoter‐specific enhancer. NSD1 may play a role in the establishment or maintenance of  IGF2 ‐DMR0 methylation during the postimplantation period.

the faseb journal

DNA methylation analysis of multiple imprinted DMRs in Sotos syndrome reveals  IGF2 ‐DMR0 as a DNA methylation‐dependent, P0 promoter‐specific enhancer