Study on heterochromatin formation at the genomic loci for immune evasion and sexual development

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03477
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49040:Parasitology-related
• Research Institution: Osaka University
• Principal Investigator: Iwanaga Shiroh 大阪大学, 微生物病研究所, 教授 (20314510)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: マラリア原虫 / ヘテロクロマチン

Outline of Final Research Achievements

AP2-HC is a heterochromatic molecule in ApiAP2 transcriptional factor family. Here we demonstrate that AP2-HC can bind to specific genomic loci near heterochromatic region in a sequence-dependent manner, including the 3’-UTR of ap2-g, the 5’ upstream of pfgdv1, and genomic loci near telomeres. This sequence-dependent binding requires another domain conserved among Plasmodium parasites in addition to the AP2 domain. LC-MS/MS analysis with proximal labeling showed that AP2-HC might interact with PfSET1and PfSwd1, which is predicted to be a component of the SET1/COMPASS complex. Subsequent ChIP-seq analysis revealed that the AP2-HC disruption diminished or eliminated the sequence-dependent recruitment of PfSwd1 to specific genomic loci, including telomeres. Therefore, AP2-HC has two binding modes, dependent and independent of a particular sequence, and it may recruit putative chromatin modifiers to specific genomic loci in a sequence-dependent manner.

Free Research Field

寄生虫学

Academic Significance and Societal Importance of the Research Achievements

マラリア原虫は多重遺伝子族によりコードされる赤血球表面抗原を使い、その発現を転換することで宿主免疫を回避する。また赤血球内での生育過程で一部の原虫内で転写因子（AP2-G）の発現活性化が起き、雌雄の生殖母体細胞へと分化する。これらの現象は同一の遺伝学的背景を持つ原虫で起こることから、エピジェネティックな制御によると考えられるが、その機構は不明のままである。本研究の成果はその解決の手がかりを与え、エピジェネティク制御という学術的な意義だけでなく、ワクチン開発、生殖母体細胞を標的とした薬剤開発に貢献し、社会的な意義がある。