2023 Fiscal Year Final Research Report
Elucidation of molecular pathogenesis of intellectual disability based on identification of target genes of epigenome modifying factor NSD1
| Project/Area Number |
20H03643
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Saga University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | ソトス症候群 / NSD1 / コンディショナルノックアウトマウス / エピゲノム / トランスクリプトーム |
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| Outline of Final Research Achievements |
Intellectual disability in Sotos syndrome, caused by haploinsufficiency of NSD1, is believed to result from abnormal formation of neural circuits, yet the molecular pathogenesis remains unknown. This study aimed to elucidate the molecular mechanisms underlying cognitive impairment using brain-specific knockout mice. Morphological analysis revealed hippocampal shrinkage, in addition to findings similar to those in humans, and behavioral analysis showed impaired spatial memory. Furthermore, increased gene expression correlated with DNA hypomethylation of promoter regions, while decreased gene expression was primarily associated with reduced H3K27Ac levels. The observed reduction in dendritic spine numbers in the dentate gyrus coincided with these gene expression changes, implying a compromised capacity for spatial learning in this murine model.
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| Free Research Field |
分子遺伝学・エピジェネティクス
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| Academic Significance and Societal Importance of the Research Achievements |
脳特異的NSD1ノックアウトマウスを用いてソトス症候群の精神発達遅滞の分子病態の解明を試みた。本マウスは、形態学的、行動学的にソトス症候群に類似した所見を呈したことから、NSD1ノックアウトに基づいた初めてのモデルマウスである。エピゲノム変化に伴って発現が上昇する遺伝子群と低下する遺伝子群を同定し、これらの遺伝子発現変化が海馬歯状回の樹状突起のスパイン数減少と関連し、空間記憶の低下が生じることが示唆され、精神発達遅滞の分子病態を解明する端緒を得た。本マウスをさらに解析することにより精神発達遅滞の分子病態の詳細を明らかにすることが可能と思われる。
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