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<p>A key challenge of the modern genomics era is developing empirical data-driven representations of gene function. Here we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-wide genotype–phenotype maps comprising CRISPR–Cas9-based knockouts of &gt;20,000 genes in &gt;30 million cells. Our optical pooled cell profiling platform (PERISCOPE) combines a destainable high-dimensional phenotyping panel (based on Cell Painting) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This perturbation atlas comprises high-dimensional phenotypic profiles of individual cells with sufficient resolution to cluster thousands of human genes, reconstruct known pathways and protein–protein interaction networks, interrogate subcellular processes and identify culture media-specific responses. Using this atlas, we identify the poorly characterized disease-associated TMEM251/LYSET as a Golgi-resident transmembrane protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes. In sum, this perturbation atlas and screening platform represents a rich and accessible resource for connecting genes to cellular functions at scale.</p>

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A genome-wide atlas of human cell morphology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月27日

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  • Meraj Ramezani,
  • Erin Weisbart,
  • Julia Bauman,
  • Avtar Singh,
  • John Yong,
  • Maria Lozada,
  • Gregory P. Way,
  • Sanam L. Kavari,
  • Celeste Diaz,
  • Eddy Leardini,
  • Gunjan Jetley,
  • Jenlu Pagnotta,
  • Marzieh Haghighi,
  • Thiago M. Batista,
  • Joaquín Pérez-Schindler,
  • Melina Claussnitzer,
  • Shantanu Singh,
  • Beth A. Cimini,
  • Paul C. Blainey,
  • Anne E. Carpenter,
  • Calvin H. Jan,
  • James T. Neal

摘要

A key challenge of the modern genomics era is developing empirical data-driven representations of gene function. Here we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-wide genotype–phenotype maps comprising CRISPR–Cas9-based knockouts of >20,000 genes in >30 million cells. Our optical pooled cell profiling platform (PERISCOPE) combines a destainable high-dimensional phenotyping panel (based on Cell Painting) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This perturbation atlas comprises high-dimensional phenotypic profiles of individual cells with sufficient resolution to cluster thousands of human genes, reconstruct known pathways and protein–protein interaction networks, interrogate subcellular processes and identify culture media-specific responses. Using this atlas, we identify the poorly characterized disease-associated TMEM251/LYSET as a Golgi-resident transmembrane protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes. In sum, this perturbation atlas and screening platform represents a rich and accessible resource for connecting genes to cellular functions at scale.