2023 Fiscal Year Final Research Report

Mechanistic Insights into Non-Coding RNA Transcription and Super-Enhancer Activation via Control Region Mutations

Research Project

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Project/Area Number	21H02878
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 52050:Embryonic medicine and pediatrics-related
Research Institution	Tokyo Medical and Dental University
Principal Investigator	Isoda Takeshi 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (80815225)
Co-Investigator(Kenkyū-buntansha)	高木正稔東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (10406267) 森尾友宏東京医科歯科大学, 大学院医歯学総合研究科, 教授 (30239628)
Project Period (FY)	2021-04-01 – 2024-03-31
Keywords	非コードRNA / ThymoD / エピジェネティクス / 白血病 / 免疫不全症 / メチル化 / 転写 / ゲノムの3次元構造
Outline of Final Research Achievements	T cells play a central role in immune function. The Bcl11b transcription factor is essential for T cell lineage commitment, and its expression is regulated by the transcription of the non-coding RNA ThymoD (thymocyte differentiation factor) located on a super-enhancer of Bcl11b. Disruption of ThymoD transcription is associated with the development of combined immunodeficiency diseases and T cell lineage hematological malignancy. This study aims to identify the ThymoD region in humans and evaluate how ThymoD transcription regulates methylation, chromatin modifications, and three-dimensional structure at the transcribed region. We identified the ThymoD region in humans and aimed to elucidate the mechanisms of super-enhancer activation. Our findings suggest that transcription is crucial for maintaining the genome structure of ThymoD-BCL11B region and that the genomic structure varies depending on the subtype of leukemia.
Free Research Field	胎児医学および小児成育学関連
Academic Significance and Societal Importance of the Research Achievements	ゲノムの3次元構造の評価は、白血病、そのほかの腫瘍、遺伝性疾患の分類に寄与できると想定される。今回、ヒトThymoD領域を同定でき、5種類のＢ細胞系・Ｔ細胞系白血病細胞株及び正常Ｔ細胞を用いた構造解析で、同領域の近接性を示すtopologically associated domain (TAD)に違いがあることが示された。転写に影響する異なる阻害剤を用いた検討で、新生RNA転写を抑制すると、TAD構造および周囲のクロマチン修飾に影響を与えることが判明した。ThymoD転写、DNAメチル化、クロマチン制御、TAD形成の制御機構を理解することで、疾患の分類、治療応用への展開へとつなげていく。