2. Academic Validation
  3. Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release

Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release

  • Nature. 2024 Mar 13. doi: 10.1038/s41586-024-07172-y.
Turan Tufan 1,  Gamze Comertpay 1,  Ambra Villani 2,  Geoffrey M Nelson 3,  Marina Terekhova 1,  Shannon Kelley 1,  Pavel Zakharov 1,  Rochelle M Ellison 1,  Oleg Shpynov 1 4,  Michael Raymond 5,  Jerry Sun 1,  Yitan Chen 1,  Enno Bockelmann 2,  Marta Stremska 1,  Lance W Peterson 6,  Laura Boeckaerts 7,  Seth R Goldman 3,  J Iker Etchegaray 1,  Maxim N Artyomov 1,  Francesca Peri 2,  Kodi S Ravichandran 8 9 10
Affiliations

Affiliations

  • 1 Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  • 2 Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 4 JetBrains Research, Munich, Germany.
  • 5 Department of Neuroscience and MIC, University of Virginia, Charlottesville, VA, USA.
  • 6 Department of Pediatrics, Division of Rheumatology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.
  • 7 Unit for Cell Clearance in Health and Disease, VIB-UGent Center for Inflammation Research and the Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
  • 8 Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. kodi@wustl.edu.
  • 9 Department of Neuroscience and MIC, University of Virginia, Charlottesville, VA, USA. kodi@wustl.edu.
  • 10 Unit for Cell Clearance in Health and Disease, VIB-UGent Center for Inflammation Research and the Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. kodi@wustl.edu.
PMID: 38480883 DOI: 10.1038/s41586-024-07172-y
Abstract

During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis1. How macrophages may rapidly adapt their transcription to achieve continuous corpse uptake is incompletely understood. Transcriptional pause/release is an evolutionarily conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20-60 nucleotides, is paused for minutes to hours and is then released to make full-length mRNA2. Here we show that macrophages, within minutes of corpse encounter, use transcriptional pause/release to unleash a rapid transcriptional response. For human and mouse macrophages, the Pol II pause/release was required for continuous efferocytosis in vitro and in vivo. Interestingly, blocking Pol II pause/release did not impede Fc receptor-mediated phagocytosis, yeast uptake or Bacterial phagocytosis. Integration of data from three genomic approaches-precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq)-on efferocytic macrophages at different time points revealed that Pol II pause/release controls expression of select transcription factors and downstream target genes. Mechanistic studies on transcription factor EGR3, prominently regulated by pause/release, uncovered EGR3-related reprogramming of other macrophage genes involved in Cytoskeleton and corpse processing. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Furthermore, microglia from egr3-deficient zebrafish embryos displayed reduced phagocytosis of apoptotic neurons and fewer maturing phagosomes, supporting defective corpse processing. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.

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