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Rapid unleashing of macrophage efferocytic capacity via transcriptional pause release.

Turan TufanGamze ComertpayAmbra VillaniGeoffrey M NelsonMarina TerekhovaShannon KelleyPavel ZakharovRochelle M EllisonOleg ShpynovMichael RaymondJerry SunYitan ChenEnno BockelmannMarta StremskaLance W PetersonLaura BoeckaertsSeth R GoldmanJ Iker EtchegarayMaxim N ArtyomovFrancesca PeriKodi S Ravichandran
Published in: Nature (2024)
During development, inflammation or tissue injury, macrophages may successively engulf and process multiple apoptotic corpses via efferocytosis to achieve tissue homeostasis 1 . 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 mRNA 2 . 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.
Keyphrases
  • transcription factor
  • gene expression
  • single cell
  • cell death
  • dna binding
  • genome wide
  • public health
  • electronic health record
  • heat shock
  • poor prognosis
  • copy number
  • rna seq
  • heat stress
  • neuropathic pain