A genome-wide CRISPR screen identifies the TNRC18 gene locus as a regulator of inflammatory signaling

Fedik Rahimov (), Sujana Ghosh, Sakina Petiwala, Mary Schmidt, Eugene Nyamugenda, Manman Shi, Jason Tam, Daniel Verduzco, Sanjana Singh, Victor Avram, Apexa Modi, Celso A. Espinoza, Charles Lu, Jing Wang, Ashleigh Keller, Michael Macoritto, Naim Al Mahi, Tifani Anton, Namjin Chung, Michael J. Flister, Kanstantsin V. Katlinski, Amlan Biswas, Anneke I. den Hollander, Jeffrey F. Waring and Joshua D. Stender ()
Additional contact information
Fedik Rahimov: AbbVie Inc., Genomics Research Center
Sujana Ghosh: AbbVie Inc., Genomics Research Center
Sakina Petiwala: AbbVie Inc., Genomics Research Center
Mary Schmidt: AbbVie Inc., Genomics Research Center
Eugene Nyamugenda: AbbVie Inc., Genomics Research Center
Manman Shi: AbbVie Inc., Genomics Research Center
Jason Tam: AbbVie Inc., Immunology Discovery Research
Daniel Verduzco: AbbVie Inc., Genomics Research Center
Sanjana Singh: AbbVie Inc., Genomics Research Center
Victor Avram: AbbVie Inc., Genomics Research Center
Apexa Modi: AbbVie Inc., Genomics Research Center
Celso A. Espinoza: AbbVie Inc., Genomics Research Center
Charles Lu: AbbVie Inc., Genomics Research Center
Jing Wang: AbbVie Inc., Genomics Research Center
Ashleigh Keller: AbbVie Inc., Genomics Research Center
Michael Macoritto: AbbVie Inc., Genomics Research Center
Naim Al Mahi: AbbVie Inc., Genomics Research Center
Tifani Anton: AbbVie Inc., Genomics Research Center
Namjin Chung: AbbVie Inc., Genomics Research Center
Michael J. Flister: AbbVie Inc., Genomics Research Center
Kanstantsin V. Katlinski: AbbVie Inc., Immunology Discovery Research
Amlan Biswas: AbbVie Inc., Immunology Discovery Research
Anneke I. den Hollander: AbbVie Inc., Genomics Research Center
Jeffrey F. Waring: AbbVie Inc., Genomics Research Center
Joshua D. Stender: AbbVie Inc., Genomics Research Center

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Interleukin-1β (IL-1β) is dysregulated in chronic inflammatory diseases, yet the genetic factors influencing IL-1β production remain largely unknown. Myeloid-derived cells are the primary producers of IL-1β, which prompted a genome-wide CRISPR knockout screen in the human myeloid-derived U937 cells treated with lipopolysaccharide (LPS) to mimic inflammatory conditions and sorted for high and low intracellular IL-1β levels. A total of 295 genes are identified as regulators of IL-1β production, with 57 overlapping loci associated with inflammatory diseases, including the TNRC18 gene locus associated with multiple diseases in the Finnish population. U937 cells engineered with the Finnish-enriched rs748670681 risk allele demonstrate decreased expression of TNRC18 and an adjacent gene WIPI2, reduction in LPS-dependent gene activation and cytokine production, but elevation of interferon-responsive gene programs. Transcriptomic profiles for individual knockouts of TNRC18 and WIPI2 attribute the loss of LPS-dependent signaling primarily to TNRC18, which occurs through the modulation of H3K27 acetylation around inflammatory regulatory regions via TNRC18 and its protein interaction network. In contrast, the loss of WIPI2 is characterized by an exacerbation of interferon signaling. These findings delineate the global regulatory mechanisms of IL-1β production and provide molecular insights to the role of the rs748670681 variant in inflammatory diseases.

Date: 2025
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DOI: 10.1038/s41467-025-65277-y

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