Elucidation of MDS pathogenesis based on understanding the roles of newly identified SWI/SNF complex

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03717
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Foundation for Biomedical Research and Innovation at Kobe
• Principal Investigator: Inoue Daichi 公益財団法人神戸医療産業都市推進機構, その他部局等, 研究員(副センター長・部長クラス) (80735746)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: BRD9 / 造血幹細胞 / SWI/SNF複合体 / クロマチンリモデリング / CTCF / RNAスプライシング

Outline of Final Research Achievements

Beyond DNA mutations, post-transcriptional regulatory mechanisms at the RNA level are gaining significant attention in cancer research. Notably, tumor cell-specific RNA dysregulation is emerging as a critical area of investigation, particularly given that RNA splicing-related gene mutations have been identified in approximately half of myelodysplastic syndromes (MDS). Despite this, the understanding of such dysregulation remains limited. In this study, we investigated the phenomenon wherein BRD9, a vital component of the novel SWI/SNF complex responsible for chromatin remodeling, is frequently lost in cancer cells due to the aberrant splicing. Utilizing knockout mice as our primary model, we concentrated on elucidating the role of BRD9 in hematopoietic stem cells (HSCs). Our research uncovered how aberrant splicing of BRD9 affects the cell fate of HSCs through the chromatin regulation.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究成果はゲノム変異を認めないBRD9遺伝子が転写後RNAレベルでの制御破綻によって機能喪失をきたし、それに伴うクロマチン状態の改変が造血幹細胞の新たな運命制御を示唆する知見と言える。このように、がんにおいては、DNAレベルの異常を伴わなくとも、他の重要な遺伝子の転写を脱制御するような現象が転写制御因子のRNAレベルで起こりうることを実験的に証明した成果と言え、今後の病態理解や治療応用につながる内容と言える。