Nature biotechnologyJul 1, 2026

A large-scale map of gene activity control in human stem cells

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 2, 2026

Abstract

An atlas mapping transcriptional phenotypes associated with 11,692 perturbed genes was generated using over 2.5 million single cells.

The cell atlas reveals correlations among perturbed phenotypes, leading to a comprehensive map of the pluripotent state.
Functionally related protein complexes are richly recapitulated within this cell map.
Metabolic factor ZBTB41 and pluripotency regulator RNF7 were identified and their functions validated through various assays.
A genome-scale screen of A-to-I RNA-editing modulators was performed, highlighting DBR1 as a potent regulator.

Simplified

Comprehensively mapping the relationship between genotype and phenotype offers essential insights into how a cell's state arises from its genetic components. Toward this goal, we generated an expressed genome-scale CRISPRi perturbation cell atlas in KOLF2.1J human induced pluripotent stem cells, mapping transcriptional phenotypes associated with 11,692 perturbed genes across >2.5 million single cells. Using correlations among perturbed phenotypes, we created a cell map of the pluripotent state, demonstrating rich recapitulation of functionally related protein complexes. We then explored the atlas to uncover metabolic factor ZBTB41 and pluripotency regulator RNF7, validating their functions through metabolic tracing, immunofluorescence and protein-protein interaction assays. Lastly, we leveraged the atlas to generate a genome-scale screen of A-to-I RNA-editing modulators assayed through direct transcriptome-wide RNA editing, uncovering and mechanistically validating DBR1 as a potent regulator. Taken together, our data provide a comprehensive resource for interrogating the regulatory networks governing pluripotency, which is accessible at https://y-doctor.github.io/KOLF2.1J_Perturbation_Cell_Atlas/ .

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A large-scale map of gene activity control in human stem cells

Abstract

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