Mapping transcription factor functions in astrocytes using in vivo gain-of-function Perturb-seq

  • Science. 2026 Apr 23;392(6796):eadw2156. doi: 10.1126/science.adw2156.
Liansheng Zhang  #  1 ,  Qi Ma  #  1  2 ,  Xiangrui Kong  1 ,  Weijuan Zou  #  3 ,  Bo Wang  #  1 ,  Bin Wu  #  4 ,  Shicheng Cai  1  2 ,  Tao Bai  1 ,  Runlin Tan  3 ,  Ziji Dai  1  2 ,  Xingyu Liu  1 ,  Zhiheng Jia  1  2 ,  Meimei Zhang  5 ,  Tianwen Li  6 ,  Yuanyi Zheng  3 ,  Xinde Hu  5 ,  Jianrong Wu  3 ,  Zhengzheng Xu  1 ,  Haibo Zhou  1  7  8  9
Affiliations
  • 1. Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 2. University of Chinese Academy of Sciences, Beijing, China.
  • 3. Shanghai Key Laboratory of Neuro-Ultrasound for Diagnosis and Treatment, Department of Ultrasound in Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4. Department of Neurology, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 5. Genemagic Biosciences Co., Ltd., Shanghai, China.
  • 6. Department of Neurosurgery, National Center for Neurological Disorders, National Key Laboratory for Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China.
  • 7. Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
  • 8. Shanghai Key Laboratory of Precision Gene Editing and Clinical Translation, Shanghai, China.
  • 9. China-Hungary Belt-and-Road Joint laboratory on Brain Science, Shanghai, China.
  • # Contributed equally.
PMID: 42024736 DOI: 10.1126/science.adw2156
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.

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