研究团队开发了一种体内功能获得性紊乱序列平台，称为iGOF-紊乱序列，用于构建星形胶质细胞中约1000个转录因子（TFs）的功能图谱，星形胶质细胞是许多脑功能所必需的细胞类型。然后，研究组确定了协同功能模块，注释了未表征的TF，并预测了与疾病相关的TF密度。
此外，在单主题神经炎症模型中进行的iGOF-Perturb-seq发现Ferd3l是一种治疗候选者，并且星形胶质细胞特异性过表达Ferd3l减轻了小鼠阿尔茨海默病的症状。本研究为了解体内基因调控和疾病机制以及确定不同脑疾病的潜在治疗靶点提供了依据。
据悉，结合高通量筛选和细胞类型特异性读数的体内方法可以阐明复杂组织中的基因型-表型关系。
附：英文原文
Title: Mapping transcription factor functions in astrocytes using in vivo gain-of-function Perturb-seq
Author: Liansheng Zhang, Qi Ma, Xiangrui Kong, Weijuan Zou, Bo Wang, Bin Wu, Shicheng Cai, Tao Bai, Runlin Tan, Ziji Dai, Xingyu Liu, Zhiheng Jia, Meimei Zhang, Tianwen Li, Yuanyi Zheng, Xinde Hu, Jianrong Wu, Zhengzheng Xu, Haibo Zhou
Issue&Volume: 2026-04-23
Abstract: An in vivo approach combining high-throughput screening with cell type–specific readouts could enable elucidation of genotype-phenotype relationships in complex tissues. We developed an in vivo gain-of-function Perturb-seq platform, termed iGOF–Perturb-seq, to build a functional atlas of ~1000 transcription factors (TFs) in astrocytes, a cell type essential to many brain functions. We then identified cofunctional modules, annotated uncharacterized TFs, and predicted disease-associated TF clusters. Furthermore, iGOF–Perturb-seq performed in a mouse neuroinflammatory model identified Ferd3l as a therapeutic candidate, and astrocyte-specific overexpression of Ferd3l alleviated Alzheimer’s disease symptoms in mice. This study provides resources for understanding gene regulation and disease mechanisms in vivo and for identifying potential therapeutic targets for different brain diseases.
DOI: adw2156
Source: https://www.science.org/doi/10.1126/science.adw2156