Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors

Cell Death Dis. 2015 Jun 18;6(6):e1793. doi: 10.1038/cddis.2015.159.

Abstract

Developmental exposure to excess glucocorticoids (GCs) has harmful neurodevelopmental effects, which include persistent alterations in the differentiation potential of embryonic neural stem cells (NSCs). The mechanisms, however, are largely unknown. Here, we investigated the effects of dexamethasone (Dex, a synthetic GC analog) by MeDIP-like genome-wide analysis of differentially methylated DNA regions (DMRs) in NSCs isolated from embryonic rat cortices. We found that Dex-induced genome-wide DNA hypomethylation in the NSCs in vitro. Similarly, in utero exposure to Dex resulted in global DNA hypomethylation in the cerebral cortex of 3-day-old mouse pups. Dex-exposed NSCs displayed stable changes in the expression of the DNA methyltransferase Dnmt3a, and Dkk1, an essential factor for neuronal differentiation. These alterations were dependent on Tet3 upregulation. In conclusion, we propose that GCs elicit strong and persistent effects on DNA methylation in NSCs with Tet3 playing an essential role in the regulation of Dnmt3a and Dkk1. Noteworthy is the occurrence of similar changes in Dnmt3a and Dkk1 gene expression after exposure to excess GC in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cells, Cultured
  • DNA (Cytosine-5-)-Methyltransferases / biosynthesis
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation / genetics*
  • DNA-Binding Proteins / metabolism*
  • Dexamethasone / pharmacology*
  • Dioxygenases
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Glucocorticoids / pharmacology*
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Dkk1 protein, rat
  • Glucocorticoids
  • Intercellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Dexamethasone
  • Dioxygenases
  • Tet3 protein, mouse
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A