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FOXP3 Expression Depends on Cell-Type Specific Cis-Regulatory Element and Transcription Factor Circuitry [CRISPRoff_RNA-seq]

GSE305062 Homo sapiens Expression profiling by high throughput sequencing 6 samples Submitted 2025/11/13 Platform GPL34281
Summary
FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Tregs). While mice exclusively express FOXP3 in Tregs, humans also transiently express FOXP3 in stimulated conventional CD4+ T cells (Tconvs). Mechanisms governing these distinct expression patterns remain unknown. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Tregs and Tconvs to discover cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv FOXP3 expression depended on a subset of Treg CREs and Tconv-selective positive (NS+) and negative (NS-) CREs. Combinatorial silencing of Tconv CREs revealed their epistatic logic. The CREs are occupied and regulated by TFs we identified as critical regulators of FOXP3. Finally, mutagenesis of murine NS- revealed that it is critical for restriction of FOXP3 expression to Tregs. We discover CRE and TF circuitry controlling FOXP3 expression and reveal cell and species-specific regulation of a gene indispensable to immune homeostasis.
Published in
FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry
Umhoefer JM, Arce MM, Kasinathan S et al. · Immunity 2026 · PMID 41237776 · doi:10.1016/j.immuni.2025.10.020
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Also filed as BioProject PRJNA1304380 and SRA study SRP608257. Searching any of these in the dataset finder brings you back here.

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