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疾病相关的微质激活程序的转录调节

Amanda McQuade¹, Reet Mishra^1,2, Venus Hagan¹

¹Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.

bioRxiv : the preprint server for biology

|November 24, 2025

概括

研究人员使用CRISPR屏幕在脑免疫细胞中确定了微质激活状态的关键调节者. 这一发现为通过控制特定的微质功能来开发针对大脑疾病的向治疗提供了一个框架.

科学领域:

神经免疫学神经免疫学
细胞和分子神经科学

背景情况:

微质,大脑的先天免疫细胞,表现出各种激活状态,对神经健康和疾病至关重要.
异常的微质激活与各种大脑疾病有关,强调调节这些状态的治疗潜力.

研究的目的:

确定控制特定微质激活状态的新型调节剂.
建立治疗指导微质激活治疗大脑疾病治疗的框架.

主要方法:

在诱导多能干细胞 (iPSC) 衍生微质中进行了CRISPR干扰 (CRISPRi) 选,以确定六种不同的微质状态的抑制剂和激活剂.
对于每个状态,都确定了转录调节剂,并进一步使用单细胞转录组学和细胞表面蛋白学在两个iPSC衍生的微细胞模型中进行了表征.
进行了选定的调节器的功能性表征,包括STAT2,PRDM1和DNMT1.

主要成果:

识别控制特定微质激活状态的转录调节剂.
发现STAT2倒置抑制了干扰素反应和溶酶体功能.
降低PRDM1促进了与疾病相关的,富含脂质的特征和增强的细胞化.
DNMT1的淘汰导致全球低甲基化,激活干扰素信号的负调节者.

结论:

该研究提供了对微质激活状态的调节者的全面资源.
这些发现为选择性调节微质激活状态及其功能提供了战略框架.
已识别的调节器具有开发用于治疗大脑疾病的新疗法策略的潜力.

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