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在精神疾病中SMC3/CEBPB对PAXIP1-AS1的基因特异调节驱动小鼠的突触和行为功能障碍

Chaoying Ni^1,2, He Chen^1,3, Qiaqi Chen^1,2

¹Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, and School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|September 5, 2025

概括

基因变异通过改变基因表达影响精神障碍,如精神分裂症和双相情感障碍. 一种特定的变异,rs112651172,影响长非编码RNAPAXIP1-AS1,影响大脑功能和行为.

科学领域:

神经遗传学
分子精神病学
表观遗传学

背景情况:

精神分裂症 (SCZ) 和双相情感障碍 (BPD) 是高度遗传的复杂精神疾病.
非编码的遗传变体越来越多地通过表观遗传机制 (如异位基因特异表达) 参与疾病风险.

研究的目的:

通过使用异调单胞胎双胞胎对来研究非编码变体和ASE在SCZ和BPD中的作用.
确定与精神疾病相关的特定遗传变异和长非编码RNA (lncRNA).

主要方法:

对SCZ或BPD不一致的单胞胎双胞胎的全基因组和转录组分析.
使用基于细胞的测试和小鼠模型对已识别的ASE变体进行功能验证.
对死后脑组织数据集的分析 (PsychENCODE,LIBD).

主要成果:

非编码变异导致受影响个体与未受影响的双胞胎之间的 lncRNA ASE 模式差异.
这种 rs112651172 变异通过异位基因特异转录因子结合 (SMC3/ CEBPB) 调节PAXIP1- AS1 表达,患者的 G 异位基因上调.
在SCZ和BPD脑组织中观察到PAXIP1- AS1表达的升高;在小鼠中,其过度表达导致了类似精神病的行为和认知缺陷.
通过PAXIP1-AS1上调CNTNAP3,而CNTNAP3倒置反转了观察到的表型.

结论:

rs112651172变异是一种功能调节元件,通过ASE驱动的lncRNA失调将非编码遗传风险与精神病类型联系起来.
对PAXIP1-AS1及其下游点CNTNAP3的调节失调有助于SCZ和BPD的发病.
PAXIP1- AS1 和 CNTNAP3 是 SCZ 和 BPD 的潜在治疗点.

关键词:

美国在CNTNAP3中其他国家双极性疾病在cRNA 一个双胞胎精神分裂症

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