Involvement of the transcription complex in higher brain function

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurophysiology / General neuroscience
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Ohnishi Tetsuo 国立研究開発法人理化学研究所, 脳神経科学研究センター, 副チームリーダー (80373281)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 均衡型転座 / 統合失調症 / 双極性障害 / ChIP seq / マイクロアレイ / ノックアウトマウス / 転写因子

Outline of Final Research Achievements

We have reported a schizophrenia patient with a balanced translocation between chromosomes 4 and 13, and found that the breakpoint within chromosome 4 locates proximately to the promoter region of the LDB2. In the present study, we revealed that Ldb2 knockout mice displayed various behavioral and functional deficits relevant across mental disorders. We showed potential involvement of dysregulated synaptic plasticity controlled by the immediate early gene product Arc in the abnormal phenotypes. Ldb2 KO mice exhibited dysregulated gene expression patterns, and we showed that LDB2 binds to >10,000 genomic sites. Consensus binding sequences of the EGR transcription factors, another immediate early gene product, were enriched in the center of concentrated sequences. Collectively, the current study suggests that dysregulation in the Arc-related biological processes and gene expression control by LDB2 and EGR underlie the pathogenic mechanism in a subset of mental disorders.

Free Research Field

分子神経科学

Academic Significance and Societal Importance of the Research Achievements

本研究では、４番染色体と13番染色体の間の均衡型転座を持つ稀な統合失調症症例に着目し、遺伝子ノックアウト動物の解析等からその原因遺伝子がLDB2である可能性、転写調節因子と考えられるLDB2が制御する遺伝子発現ネットワークを明らかにすることができた。その遺伝子発現ネットワークの異常を介して、統合失調症や双極性障害における一部集団の病態生理を分子レベルで理解することができる可能性を秘めるものであり、極めて貴重な研究成果となった。また本研究の成果は、精神疾患のバイオマーカー研究にも貴重な情報を提供した。