Molecular mechanisms by which aberrant hypermethylation expands beyond boundaries in Imprinting diseases
| Project/Area Number |
21K19451
|
|---|
| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
Medium-sized Section 52:General internal medicine and related fields
|
|---|
| Research Institution | Saga University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2021-07-09 – 2023-03-31
|
| Project Status |
Completed (Fiscal Year 2022)
|
| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2022: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2021: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
|
|---|
| Keywords | インプリンティング疾患 / Beckwith-Wiedemann症候群 / インプリティング制御領域 / DNAメチル化 / SOX2/OCT4 / CTCF / 過成長 / インプリンティング制御領域 / DNAメチル化バウンダリー / ゲノムインプリンティング |
|---|
| Outline of Research at the Start |
本研究では、DNAme boundaryの特徴を明らかにし、メチル化伸展の分子機構を解明する。BWSは、ICR1の異常高メチル化で発症する。母性アレルICR1の非メチル化にはOCT4とCTCFの結合が重要であり、OCT4/SOX2結合部位の変異が母から子に伝達されると、異常高メチル化がより広範囲・高度になる。マウスでもICR1に同様の変異を導入したところ、DNAme boundaryを同定した。このマウスを用いてDNAme boundaryの欠失とヒストン修飾解析、CTCF結合部位への変異導入を行い、メチル化伸展の分子機構を解明する。
|
| Outline of Final Research Achievements |
Beckwith-Wiedemann syndrome (BWS), an imprinting disorder, is caused by aberrant hypermethylation at the ICR1. Methylation status at the normal ICR1 differs between the two parental alleles, and the maintenance of the differentially methylation relies on the interaction of specific binding sites, namely the SOX2/OCT4 binding sites (SOBS) and the CTCF binding sites (CBS). However, the underlying molecular mechanisms remain elusive. In this study, we generated a panel of mutant mice with mutations introduced into the SOBS and four CBS sites of mouse ICR1 (10 strains) to investigate their impact. Our findings indicate that the key regions responsible for ICR1 methylation maintenance are SOBS and CBS3. It is suggested that disruption of SOX2/OCT4 and CTCF binding to these regions leads to chromatin structural changes, resulting in aberrant hypermethylation and subsequent alterations in gene expression that contribute to the observed phenotypic manifestations including overgrowth.
|
| Academic Significance and Societal Importance of the Research Achievements |
母性ICR1のメチル化維持には、SOBSとCBS3が重要であることが判明し、これまで不明であったSOBSとCBSの協働分子機構の一端が解明できた。BWS発症につながる胎生期のメチル化異常の発生機構の解明につながる。また、遺伝子診断、治療、予防の技術開発の基盤となる。
|
Report
(3 results)
Research Products
(37 results)
-
-
-
-
-
-
-
-
-
-
[Journal Article] An analysis of the demographic history of the risk allele R4810K in RNF213 of moyamoya disease.2021
Author(s)
K. Koganebuchi, K. Sato, K. Fujii, T. Kumabe, K. Haneji, T. Toma, H. Ishida, K. Joh, H. Soejima, S. Mano, M. Ogawa, H. Oota
-
Journal Title
Annals of Human Genetics
Volume: 1-12
Issue: 5
Pages: 1-12
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
-
[Journal Article] TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients.2021
Author(s)
Mori H, Takahashi H, Mine K, Higashimoto K, Inoue K, Kojima M, Kuroki S, Eguchi T, Ono Y, Inuzuka S, Soejima H, Nagafuchi S, Anzai K.
-
Journal Title
Genes (Basel).
Volume: 12
Issue: 3
Pages: 400-400
DOI
Related Report
Peer Reviewed / Open Access
-
-
-
-
-
[Presentation] Aberrant hypomethylation of imprinted differentially methylated regions is involved in biparental placental mesenchymal dysplasia.2022
Author(s)
Aoki S, Higashimoto K, Hidaka H, Ohtsuka Y, Aoki S, Mishima H, Yoshiura KI, Nakabayashi K, Hata K, Yatsuki H, Hara S, Ohba T, Katabuchi H, Soejima H.
Organizer
European Society of Human Genetics 2022 Hybrid Conference.
Related Report
Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
