| Project/Area Number |
18K14673
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 43050:Genome biology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Sakata Toyonori 東京大学, 定量生命科学研究所, 特任助教 (40795530)
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | コヒーシン / コヒーシンローダー / スーパーエンハンサー / CdLS / BRD4 / メディエーター / 染色体高次構造 / Hi-C / エンハンサー / 転写 |
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| 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 mis-regulation of genes mediated by cohesin and its loader, how these factors regulate transcription remains to be unclear.
To approach this point, we performed ChIP-seq, RNA-seq and Hi-C analysis using CdLS patient cell and culture cell lines with mutations in NIPBL gene. We detected differentially expressed genes (DEGs) in these cells and these DEGs were related to the developmental cell process. Moreover, we found down-DEGs were located near super-enhancers (SEs) and chromatin binding of cohesin and cohesin loader was reduced at SEs and chromatin binding of transcriptional co-factors, BRD4 and MED1 was also reduced. Taken together, we currently speculate reduction of these factors at SEs could result in weakened enhancer activity and finally induces reduced expression of nearby genes related to the developmental cell process.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、コヒーシン複合体とそのローダーはBRD4やメディエーター複合体といった転写のコファクターと協調して、スーパーエンハンサー近傍の発生関連遺伝子群の発現を促進していることが示唆された。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やBRD4遺伝子の変異によってCornelia de Lange Syndrome（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。
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