title: Loss of CpG methylation is strongly correlated with loss of histone H3 lysine 9 methylation at DMR-LIT1 in patients with Beckwith-Wiedemann syndrome.
abstract: To clarify the chromatin-based imprinting mechanism of the p57(KIP2)/LIT1 subdomain at chromosome 11p15.5 and the mouse ortholog at chromosome 7F5, we investigated the histone-modification status at a differentially CpG methylated region of Lit1/LIT1 (DMR-Lit1/LIT1), which is an imprinting control region for the subdomain and is demethylated in half of patients with Beckwith-Wiedemann syndrome (BWS). Chromatin-immunoprecipitation assays revealed that, in both species, DMR-Lit1/LIT1 with the CpG-methylated, maternally derived inactive allele showed histone H3 Lys9 methylation, whereas the CpG-unmethylated, paternally active allele was acetylated on histone H3/H4 and methylated on H3 Lys4. We have also investigated the relationship between CpG methylation and histone H3 Lys9 methylation at DMR-LIT1 in patients with BWS. In a normal individual and in patients with BWS with normal DMR-LIT1 methylation, histone H3 Lys9 methylation was detected on the maternal allele; however, it disappeared completely in the patients with the DMR-LIT1 imprinting defect. These findings suggest that the histone-modification status at DMR-Lit1/LIT1 plays an important role in imprinting control within the subdomain and that loss of histone H3 Lys9 methylation, together with CpG demethylation on the maternal allele, may lead to the BWS phenotype.
authors.affiliation: Division of Molecular Biology & Genetics, Department of Biomolecular Sciences, Saga Medical School, Nabeshima, Saga, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Higashimoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Urano
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Sugiura
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yatsuki
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Joh
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Mayumi
authors.initials: M
authors.lastname: Iwakawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Oshimura
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Soejima
mesh_terms: D001483:Base Sequence; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D017931:DNA Primers; D015226:Dinucleoside Phosphates / Q000235:genetics*; D006657:Histones / Q000235:genetics*; D006801:Humans; D008239:Lysine; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D015226:Dinucleoside Phosphates; D006657:Histones; D008239:Lysine; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C449939:KCNQ1OT1 RNA; C015772:CpG dinucleotide