Roles of phase separation in genome biology and cancer biology

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K24694
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Review Section: Biological Sciences
• Research Institution: Nagoya University
• Principal Investigator: Suzuki Hiroshi 名古屋大学, 医学系研究科, 教授 (00587793)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ゲノム / RNA / 相分離 / エンハンサー / がん

Outline of Final Research Achievements

This study aimed to investigate the roles of (liquid-liquid) phase separation (LLPS) in regulation of regulatory elements in the genome and, particularly, super-enhancers toward better understanding of alteration in gene regulation and biomolecular condensates in cancers. By focusing on the RNA exosome, which degrades many unstable RNAs in the nucleus, we have identified the regulatory roles of the RNA exosome in regulation of super-enhancers and transcriptional condensates. We have also studied the roles of intrinsically disordered regions (IDRs), major drivers of LLPS, and extrachromosomal circular DNAs (eccDNAs) in cancer cells. Furthermore, by expanding the expertise in computational modeling in previous studies, additional collaboration project has successfully developed new CRISPR-based genome editing strategy, called “safeguard sgRNA”　strategy, which improves the safety and applicability of genome editing.

Free Research Field

ゲノム科学、RNA生物学、分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

近年の研究により、転写制御やゲノム制御において、（液液）相分離と呼ばれる現象が重要な役割を果たす可能性が示唆されている。一方で、核内で転写因子や転写調節因子からなる相分離凝集体（転写凝集体）がどのように形成され、ゲノムと相互作用し、遺伝子の発現を制御するのかという基本的な分子機構はほとんど解明されていない。本研究では、非コード領域からの転写・RNA産生がどのように転写凝集体を制御しているのかという点に注目し、転写凝集体の基本的分子メカニズムに関する重要な知見を得ることができた。さらに、天然変性領域や染色体外環状DNAに関する研究は新しいがん研究の展開やがん治療の開発につながることが期待される。