Molecular mechanisms by which aberrant hypermethylation expands beyond boundaries in Imprinting diseases

2022 Fiscal Year Final Research Report

• 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: Soejima Hidenobu 佐賀大学, 医学部, 教授 (30304885)
• Project Period (FY): 2021-07-09 – 2023-03-31
• 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

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.

Free Research Field

エピジェネティクス

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。