Single-Cell CRISPR Perturb-Seq Mapping of Non-Coding Regulatory Elements in Human Disease

Large-scale human genetics studies have shown that many risk variants for common and complex diseases sit in the non-coding genome, where they can alter enhancers, promoters, insulators, and non-coding RNAs rather than protein sequence. This has created a clear bottleneck: we can often locate a disease-associated region, but we still struggle to prove which regulatory element is causal, identify its target gene(s), and pinpoint the specific cell types and cell states where it acts. Traditional bulk assays and single-locus reporter tests give useful signals, but they often miss cell-to-cell variation, dilute rare states, and do not scale well across thousands of candidate elements.



This Research Topic, Single-Cell CRISPR Perturb-Seq Mapping of Non-Coding Regulatory Elements in Human Disease, will spotlight advances that combine CRISPR-based perturbation of regulatory DNA with single-cell readouts to generate causal, high-resolution maps from element → gene program → cellular phenotype. We welcome studies using CRISPRi/a, paired-guide deletions, base/prime editing, and variant-aware perturbations alongside Perturb-seq and related single-cell approaches (scRNA-seq, scATAC-seq, CITE-seq, multiome, spatial, and other integrative methods). Submissions may focus on disease mechanisms in immune, neurological, cardiovascular, metabolic, or cancer settings; on experimental designs that improve gRNA selection and perturbation efficiency; and on computational methods that strengthen element-to-gene assignment, integrate fine-mapping, and improve reproducibility across donors and cell types.



By bringing together experimental and computational work, this Topic aims to accelerate causal interpretation of non-coding variation, define practical standards for single-cell perturbation screens, and advance the translation of regulatory genomics into biological insight and therapeutic hypotheses.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy and Practice Reviews
• Policy Brief
• Review
• Systematic Review

Keywords: Perturb-seq, CRISPRi/CRISPRa, Non-coding variants, Enhancer–gene mapping, Single-cell multi-omics

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.