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  3. Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation

Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation

  • Cell Syst. 2025 Aug 20;16(8):101346. doi: 10.1016/j.cels.2025.101346.
Peter Traxler 1,  Stephan Reichl 2,  Lukas Folkman 3,  Lisa Shaw 4,  Victoria Fife 5,  Amelie Nemc 5,  Djurdja Pasajlic 4,  Anna Kusienicka 4,  Daniele Barreca 5,  Nikolaus Fortelny 6,  André F Rendeiro 5,  Florian Halbritter 7,  Wolfgang Weninger 4,  Thomas Decker 8,  Matthias Farlik 1,  Christoph Bock 9
Affiliations

Affiliations

  • 1 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Department of Dermatology, Vienna, Austria.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria.
  • 3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria; Southern Cross University, Faculty of Science and Engineering, Gold Coast, Australia; Griffith University, Coastal and Marine Research Centre, Gold Coast, Australia.
  • 4 Medical University of Vienna, Department of Dermatology, Vienna, Austria.
  • 5 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 6 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Center for Tumor Biology and Immunology, Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria.
  • 7 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 8 Max Perutz Labs, Vienna Biocenter Campus, Vienna, Austria; University of Vienna, Center for Molecular Biology, Department of Microbiology, Immunobiology and Genetics, Vienna, Austria.
  • 9 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria. Electronic address: cbock@cemm.oeaw.ac.at.
PMID: 40782800 DOI: 10.1016/j.cels.2025.101346
Abstract

Macrophages are innate immune cells involved in host defense. Dissecting the regulatory landscape that enables their swift and specific response to pathogens, we performed time-series analysis of gene expression and chromatin accessibility in murine macrophages exposed to various immune stimuli, and we functionally evaluated gene knockouts at scale using a combined CROP-seq and CITE-seq assay. We identified new roles of transcription regulators such as Spi1/PU.1 and JAK-STAT pathway members in immune cell homeostasis and response to pathogens. Macrophage activity was modulated by splicing proteins SFPQ and SF3B1, Histone Acetyltransferase EP300, cohesin subunit SMC1A, and mediator complex proteins MED8 and MED14. We further observed crosstalk among immune signaling pathways and identified molecular drivers of pathogen-induced dynamics. In summary, this study establishes a time-resolved regulatory map of pathogen response in macrophages, and it describes a broadly applicable method for dissecting immune-regulatory programs through integrative time-series analysis and high-content CRISPR screening. A record of this paper's transparent peer review process is included in the supplemental information.

Keywords

CROP-seq; bioinformatics; innate immunity; machine learning; macrophages; multi-omics profiling; pathogen infection; single-cell CRISPR sequencing; systems immunology; time-series analysis.

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