Epigenetic fluctuation associated with onset and severity of haploinsufficient dominant diseases

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H04755
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 42:Veterinary medical science, animal science, and related fields
• Research Institution: Meiji University
• Principal Investigator: Ohgane Jun 明治大学, 農学部, 専任教授 (50313078)
• Co-Investigator(Kenkyū-buntansha): 乾 雅史 明治大学, 農学部, 専任准教授 (20643498) ; 長嶋 比呂志 明治大学, 農学部, 専任教授 (50318664)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Keywords: エピジェネティクス / ハプロ不全 / DNAメチル化 / エピゲノム編集

Outline of Final Research Achievements

To generate mice that are heterozygous for the porcine CpG shore normal allele and the mouse null allele for the FBN1 gene locus, we established ES cells with the above genotype and are planning to generate the heterozygous mice. Furthermore, promoter assays of FBN1 revealed that the FBN1 CpG shores exhibiting fluctuations in DNA methylation, function as a proximal enhancer. Furthermore, we found that the promoter activities of the CpG island and shore are suppressed by DNA methylation. Regarding RUNX2, we introduced an epigenome editing vector that induces DNA hypermethylation into stem cells that can differentiate into chondrocytes, and demonstrated that it is possible to induce DNA hypermethylation in the Runx2 promoter.

Free Research Field

エピジェネティクス

Academic Significance and Societal Importance of the Research Achievements

ハプロ不全優性遺伝病の発症が、原因遺伝子のCpGショアでのDNAメチル化のゆらぎによって決定されることを証明するためのモデル動物作製を行った。また、作製するモデル動物を使ってDNAメチル化のゆらぎを模したDNA高メチル化および低メチル化誘導を行うためのエピゲノム編集技術の最適化を図り、培養細胞レベルでFBN1、RUNX2遺伝そプロモーター領域でのDNAメチル化改変に成功した。これらにより、将来的には効率的な病態モデル動物の作成や発症予防・治療につながる基盤技術の確立に成功した。