Gene expression control mechanism via super-enhancer by cohesin loader

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K15768
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43050:Genome biology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Sakata Toyonori 東京大学, 定量生命科学研究所, 特任助教 (40795530)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: コヒーシン / コヒーシンローダー / 染色体高次構造 / Hi-C / HiChIP / Micro-C / エンハンサー / super-enhancer

Outline of Final Research Achievements

Genes coding cohesin complex and its loader complex are mutated in Cornelia de Lange syndrome (CdLS). Although CdLS seems to be caused by misregulation of genes mediated by cohesin and its loader, how these factors regulate transcription remains to be unclear.
To approach this point, we performed Hi-C, HiChIP, and Micro-C analyses using a cohesin-depleted cell line and a CdLS patient cell line. We found that cohesin is essential for most of the enhancer-promoter loops. Moreover, we found that the super-enhancer (SE)-promoter loops at down-regulated genes in the CdLS cell line were especially weakened. Taken together with the previous results, it appears that the decrease in cohesin loader in CdLS is expected to decrease the localization of BRD4 in SE, thereby decreasing the enhancer activity, and decreasing cohesin binding, thereby reducing the contact with the promoter. As a result, the expression of neighboring genes may eventually decrease.

Free Research Field

ゲノム生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、コヒーシンが多くのエンハンサーとプロモーター間のループに必須であること、Cornelia de Lange Syndrome（CdLS）においては発現減少遺伝子において特にsuper-enhancerとプロモーター間のループが減弱していることを見出した。これまでにコヒーシン、コヒーシンローダー及びその関連遺伝子の変異によってCdLSをはじめとする発生疾患が引き起こされることが知られていることから、本研究の成果はこのような発生疾患の発症メカニズムの解明や治療法開発において大いに貢献できると考えられる。