Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation

Minglei Guo, Palsamy Periyasamy, Ke Liao, Yeon Hee Kook, Fang Niu, Shannon E. Callen, Shilpa J Buch

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Neuroinflammation plays a critical role in the development of reward-related behavior in cocaine self-administration rodents. Cocaine, one of most commonly abused drugs, has been shown to activate microglia both in vitro and in vivo. Detailed molecular mechanisms underlying cocaine-mediated microglial activation remain poorly understood. microRNAs (miRs) belonging to a class of small noncoding RNA superfamily have been shown to modulate the activation status of microglia. miR-124, one of the microglia-enriched miRs, functions as an anti-inflammatory regulator that maintains microglia in a quiescent state. To date, the possible effects of cocaine on microglial miR-124 levels and the associated underlying mechanisms have not been explored. In the current study, we demonstrated that cocaine exposure decreased miR-124 levels in both BV-2 cells and rat primary microglia. These findings were further validated in vivo, wherein we demonstrated decreased abundance of miR-124 in purified microglia isolated from cocaine-administered mice brains compared with cells from saline administered animals. Molecular mechanisms underlying these effects involved cocaine-mediated increased mRNA and protein expression of DNMTs in microglia. Consistently, cocaine substantially increased promoter DNA methylation levels of miR-124 precursors (pri-miR-124-1 and −2), but not that of pri-miR-124-3, both in vitro and in vivo. In summary, our findings demonstrated that cocaine exposure increased DNA methylation of miR-124 promoter resulting into its downregulation, which, in turn, led to microglial activation. Our results thus implicate that epigenetic modulation of miR-124 could be considered as a potential therapeutic approach to ameliorate microglial activation and, possibly, the development of cocaine addiction.

Original languageEnglish (US)
Pages (from-to)819-830
Number of pages12
JournalEpigenetics
Volume11
Issue number11
DOIs
StatePublished - Nov 1 2016

Fingerprint

DNA Methylation
Cocaine
Microglia
Down-Regulation
MicroRNAs
Small Untranslated RNA
Cocaine-Related Disorders
Self Administration
Reward
Epigenomics
Rodentia
Anti-Inflammatory Agents
Messenger RNA
Brain

Keywords

  • Cocaine
  • microglial cells
  • miR-124
  • neuroinflammation
  • promoter DNA methylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation. / Guo, Minglei; Periyasamy, Palsamy; Liao, Ke; Kook, Yeon Hee; Niu, Fang; Callen, Shannon E.; Buch, Shilpa J.

In: Epigenetics, Vol. 11, No. 11, 01.11.2016, p. 819-830.

Research output: Contribution to journalArticle

Guo, Minglei ; Periyasamy, Palsamy ; Liao, Ke ; Kook, Yeon Hee ; Niu, Fang ; Callen, Shannon E. ; Buch, Shilpa J. / Cocaine-mediated downregulation of microglial miR-124 expression involves promoter DNA methylation. In: Epigenetics. 2016 ; Vol. 11, No. 11. pp. 819-830.
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