A genome-wide atlas of human cell morphology.
Meraj RamezaniJulia R BaumanAvtar SinghErin WeisbartJohn YongMaria LozadaGregory P WaySanam L KavariCeleste DiazMarzieh HaghighiThiago Martins BatistaJoaquín Pérez-SchindlerMelina ClaussnitzerShantanu SinghBeth A CiminiPaul C BlaineyAnne E CarpenterCalvin H JanJames T NealPublished in: bioRxiv : the preprint server for biology (2023)
A key challenge of the modern genomics era is developing data-driven representations of gene function. Here, we present the first unbiased morphology-based genome-wide perturbation atlas in human cells, containing three genome-scale genotype-phenotype maps comprising >20,000 single-gene CRISPR-Cas9-based knockout experiments in >30 million cells. Our optical pooled cell profiling approach (PERISCOPE) combines a de-stainable high-dimensional phenotyping panel (based on Cell Painting 1,2 ) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This approach provides high-dimensional phenotypic profiles of individual cells, while simultaneously enabling interrogation of subcellular processes. Our atlas reconstructs known pathways and protein-protein interaction networks, identifies culture media-specific responses to gene knockout, and clusters thousands of human genes by phenotypic similarity. Using this atlas, we identify the poorly-characterized disease-associated transmembrane protein TMEM251/LYSET as a Golgi-resident protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes, showing the power of these representations. In sum, our atlas and screening technology represent a rich and accessible resource for connecting genes to cellular functions at scale.
Keyphrases
- genome wide
- single cell
- dna methylation
- protein protein
- high throughput
- copy number
- induced apoptosis
- endothelial cells
- crispr cas
- genome wide identification
- small molecule
- cell cycle arrest
- working memory
- stem cells
- gene expression
- endoplasmic reticulum stress
- patient safety
- single molecule
- open label
- signaling pathway
- binding protein
- clinical trial
- high speed
- cell death
- pi k akt
- endoplasmic reticulum