Loss of CpG Methylation Is Strongly Correlated with Loss of Histone H3 Lysine 9 Methylation at DMR-LIT1 in Patients with Beckwith-Wiedemann Syndrome

Ken Higashimoto, Takeshi Urano, Kazumitsu Sugiura, Hitomi Yatsuki, Keiichiro Joh, Wei Zhao, Mayumi Iwakawa, Hirofumi Ohashi, Mitsuo Oshimura, Norio Niikawa, Tsunehiro Mukai, Hidenobu Soejima

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

To clarify the chromatin-based imprinting mechanism of the p57 KIF2/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.

Original languageEnglish
Pages (from-to)948-956
Number of pages9
JournalAmerican Journal of Human Genetics
Volume73
Issue number4
DOIs
Publication statusPublished - 01-10-2003

Fingerprint

Beckwith-Wiedemann Syndrome
Histones
Methylation
Lysine
Histone Code
Alleles
Chromosomes
Mothers
Chromatin Immunoprecipitation
Chromatin
Phenotype

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Higashimoto, Ken ; Urano, Takeshi ; Sugiura, Kazumitsu ; Yatsuki, Hitomi ; Joh, Keiichiro ; Zhao, Wei ; Iwakawa, Mayumi ; Ohashi, Hirofumi ; Oshimura, Mitsuo ; Niikawa, Norio ; Mukai, Tsunehiro ; Soejima, Hidenobu. / Loss of CpG Methylation Is Strongly Correlated with Loss of Histone H3 Lysine 9 Methylation at DMR-LIT1 in Patients with Beckwith-Wiedemann Syndrome. In: American Journal of Human Genetics. 2003 ; Vol. 73, No. 4. pp. 948-956.
@article{57f7925820df4a81a9b17549b27849f9,
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 KIF2/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.",
author = "Ken Higashimoto and Takeshi Urano and Kazumitsu Sugiura and Hitomi Yatsuki and Keiichiro Joh and Wei Zhao and Mayumi Iwakawa and Hirofumi Ohashi and Mitsuo Oshimura and Norio Niikawa and Tsunehiro Mukai and Hidenobu Soejima",
year = "2003",
month = "10",
day = "1",
doi = "10.1086/378595",
language = "English",
volume = "73",
pages = "948--956",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "4",

}

Higashimoto, K, Urano, T, Sugiura, K, Yatsuki, H, Joh, K, Zhao, W, Iwakawa, M, Ohashi, H, Oshimura, M, Niikawa, N, Mukai, T & Soejima, H 2003, 'Loss of CpG Methylation Is Strongly Correlated with Loss of Histone H3 Lysine 9 Methylation at DMR-LIT1 in Patients with Beckwith-Wiedemann Syndrome', American Journal of Human Genetics, vol. 73, no. 4, pp. 948-956. https://doi.org/10.1086/378595

Loss of CpG Methylation Is Strongly Correlated with Loss of Histone H3 Lysine 9 Methylation at DMR-LIT1 in Patients with Beckwith-Wiedemann Syndrome. / Higashimoto, Ken; Urano, Takeshi; Sugiura, Kazumitsu; Yatsuki, Hitomi; Joh, Keiichiro; Zhao, Wei; Iwakawa, Mayumi; Ohashi, Hirofumi; Oshimura, Mitsuo; Niikawa, Norio; Mukai, Tsunehiro; Soejima, Hidenobu.

In: American Journal of Human Genetics, Vol. 73, No. 4, 01.10.2003, p. 948-956.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Loss of CpG Methylation Is Strongly Correlated with Loss of Histone H3 Lysine 9 Methylation at DMR-LIT1 in Patients with Beckwith-Wiedemann Syndrome

AU - Higashimoto, Ken

AU - Urano, Takeshi

AU - Sugiura, Kazumitsu

AU - Yatsuki, Hitomi

AU - Joh, Keiichiro

AU - Zhao, Wei

AU - Iwakawa, Mayumi

AU - Ohashi, Hirofumi

AU - Oshimura, Mitsuo

AU - Niikawa, Norio

AU - Mukai, Tsunehiro

AU - Soejima, Hidenobu

PY - 2003/10/1

Y1 - 2003/10/1

N2 - To clarify the chromatin-based imprinting mechanism of the p57 KIF2/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.

AB - To clarify the chromatin-based imprinting mechanism of the p57 KIF2/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.

UR - http://www.scopus.com/inward/record.url?scp=0142091179&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0142091179&partnerID=8YFLogxK

U2 - 10.1086/378595

DO - 10.1086/378595

M3 - Article

C2 - 12949703

AN - SCOPUS:0142091179

VL - 73

SP - 948

EP - 956

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -