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Inhibition of DNA Methylation With Zebularine Alters Lipopolysaccharide-Induced Sickness Behavior and

Stephanie M Matt1,2, Jalisa D Zimmerman2, Marcus A Lawson2

  • 1Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, United States.

Frontiers in Neuroscience
|October 4, 2018
PubMed

Insights

DNA methyltransferase (DNMT) inhibitors, like zebularine, reduce neuroinflammation by decreasing DNA methylation of the Interleukin-1 beta (IL-1β) promoter, aiding faster recovery from sickness behavior.

Area of Science:

  • Neuroscience
  • Epigenetics
  • Immunology

Background:

  • DNA methyltransferases (DNMTs) regulate brain DNA methylation dynamically.
  • DNMT inhibitors affect global DNA methylation and neural plasticity genes.
  • The impact of DNMT inhibitors on lipopolysaccharide (LPS)-induced neuroinflammation is unknown.

Purpose of the Study:

  • To investigate if the DNMT inhibitor zebularine alters sickness behavior, DNA methylation of the IL-1β promoter, and inflammatory gene expression in the hippocampus and microglia.
  • To determine the central effects of zebularine on LPS-induced neuroinflammation.

Main Methods:

  • Adult mice received intracerebroventricular (ICV) injections of zebularine before LPS administration.
  • Assessed sickness behavior (burrowing activity).
  • Analyzed DNA methylation of the IL-1β promoter using bisulfite pyrosequencing.
  • Measured gene expression of inflammatory markers, epigenetic regulators, and microglial sensome.

Main Results:

  • Zebularine treatment led to faster recovery of burrowing behavior compared to LPS-only treatment.
  • Differential gene expression of inflammatory markers, epigenetic regulators, and sensome genes was observed with zebularine alone or combined with LPS.
  • ICV zebularine decreased DNA methylation at CpG sites near the IL-1β proximal promoter, with effects sustained for 48 hours.

Conclusions:

  • Central administration of the DNMT inhibitor zebularine accelerates recovery from LPS-induced sickness behavior.
  • Decreased DNA methylation of the IL-1β promoter region by zebularine disrupts molecular mechanisms underlying neuroinflammation.
  • These findings suggest a novel therapeutic target for neuroinflammatory conditions.
Keywords:
DNA methylationDNMT inhibitorIl-1βmicrogliamouse modelsneuroimmunology

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