TY - JOUR
T1 - Inhibition of DNA methylation with zebularine alters lipopolysaccharide sickness behavior and neuroinflammation in mice
AU - Matt, Stephanie M.
AU - Zimmerman, Jalisa D.
AU - Lawson, Marcus A.
AU - Bustamante, Angela C.
AU - Uddin, Monica
AU - Johnson, Rodney W.
N1 - Funding Information:
This work was supported by NIH R01 AG16710 and the University of Illinois ACES Undergraduate Research Program.
PY - 2018/9/18
Y1 - 2018/9/18
N2 - Activity of DNA methyltransferases (DNMTs), the enzymes that catalyze DNA methylation, is dynamically regulated in the brain. DNMT inhibitors alter DNA methylation globally in the brain and at individual neural plasticity-associated genes, but how DNMT inhibitors centrally influence lipopolysaccharide (LPS)-induced neuroinflammation is not known. We investigated whether the DMNT inhibitor, zebularine, would alter sickness behavior, DNA methylation of the Il-1β promoter and expression of inflammatory genes in hippocampus and microglia. Contrary to our hypothesis that zebularine may exaggerate LPS-induced sickness response and neuroinflammation, adult mice treated with an intracerebroventricular (ICV) injection of zebularine prior to LPS had surprisingly faster recovery of burrowing behavior compared to mice treated with LPS. Further, genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were differentially expressed by zebularine alone or in combination with LPS. Bisulfite pyrosequencing revealed that ICV zebularine led to decreased DNA methylation of two CpG sites near the Il-1β proximal promoter alone or in combination with LPS. Zebularine treated mice still exhibited decreased DNA methylation 48 h after treatment when LPS-induced sickness behavior as well as hippocampal and microglial gene expression were similar to control mice. Taken together, these data suggest that decreased DNA methylation, specifically of the Il-1β promoter region, with a DNMT inhibitor in the brain disrupts molecular mechanisms of neuroinflammation.
AB - Activity of DNA methyltransferases (DNMTs), the enzymes that catalyze DNA methylation, is dynamically regulated in the brain. DNMT inhibitors alter DNA methylation globally in the brain and at individual neural plasticity-associated genes, but how DNMT inhibitors centrally influence lipopolysaccharide (LPS)-induced neuroinflammation is not known. We investigated whether the DMNT inhibitor, zebularine, would alter sickness behavior, DNA methylation of the Il-1β promoter and expression of inflammatory genes in hippocampus and microglia. Contrary to our hypothesis that zebularine may exaggerate LPS-induced sickness response and neuroinflammation, adult mice treated with an intracerebroventricular (ICV) injection of zebularine prior to LPS had surprisingly faster recovery of burrowing behavior compared to mice treated with LPS. Further, genes of inflammatory markers, epigenetic regulators, and the microglial sensory apparatus (i.e., the sensome) were differentially expressed by zebularine alone or in combination with LPS. Bisulfite pyrosequencing revealed that ICV zebularine led to decreased DNA methylation of two CpG sites near the Il-1β proximal promoter alone or in combination with LPS. Zebularine treated mice still exhibited decreased DNA methylation 48 h after treatment when LPS-induced sickness behavior as well as hippocampal and microglial gene expression were similar to control mice. Taken together, these data suggest that decreased DNA methylation, specifically of the Il-1β promoter region, with a DNMT inhibitor in the brain disrupts molecular mechanisms of neuroinflammation.
KW - DNA methylation
KW - DNMT inhibitor
KW - Il-1β
KW - Microglia
KW - Mouse models
KW - Neuroimmunology
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U2 - 10.3389/fnins.2018.00636
DO - 10.3389/fnins.2018.00636
M3 - Article
C2 - 30279646
AN - SCOPUS:85055132408
VL - 12
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
SN - 1662-4548
IS - SEP
M1 - 636
ER -