Premium
Oct motif variants in Beckwith–Wiedemann syndrome patients disrupt maintenance of the hypomethylated state of the H19/IGF2 imprinting control region
Author(s) -
Kubo Shuichi,
Murata Chihiro,
Okamura Hanayo,
Sakasegawa Taku,
Sakurai Chiye,
Hatsuzawa Kiyotaka,
Hori Naohiro
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.13750
Subject(s) - imprinting (psychology) , beckwith–wiedemann syndrome , dna methylation , genomic imprinting , methylation , biology , epigenetics , demethylation , genetics , single nucleotide polymorphism , dna , gene , gene expression , genotype
The methylation status of imprinting control center 1 (IC1) regulates the monoallelic transcription of H19 and Igf2 in mammalian cells. Several single nucleotide variants in Oct motifs within IC1 occur in patients with Beckwith–Wiedemann syndrome (BWS) who have hypermethylated maternal IC1. However, the importance of Oct motifs in the regulation of IC1 methylation status remains unclear. Here, we demonstrate that three variants found in BWS (BWS variants) suppress intensive induction of DNA demethylation, whereas consensus disruption of motifs unrelated to BWS only slightly affects the induction of demethylation. BWS variants reduce DNA demethylation levels and trigger the accumulation of DNA methylation downstream of the IC1 transgenes. Thus, the risk of IC1 hypermethylation is associated with inhibitory levels of Oct motif‐dependent hypomethylation maintenance activities.