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<p>The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to <i>Citrobacter rodentium</i> infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a –2-kb <i>cis</i>-regulatory element in the <i>Rorc</i> gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.</p>

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Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt

  • 期刊论文

  • 发表日期：

    2025年8月13日

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  • Bishan Bhattarai,
  • Alina Ulezko Antonova,
  • Jose L. Fachi,
  • Leone S. Hopkins,
  • Matthew V. D. McCullen,
  • Ankita Saini,
  • Sarah de Oliveira,
  • Wandy L. Beatty,
  • Erik S. Musiek,
  • Vijay K. Kuchroo,
  • Mitchell A. Lazar,
  • Eugene M. Oltz,
  • Marco Colonna

摘要

The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a –2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.