The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor.

TitleThe methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor.
Publication TypeJournal Article
Year of Publication2014
AuthorsWeaver ICG, Hellstrom IC, Brown SE, Andrews SD, Dymov S, Diorio J, Zhang T-Y, Szyf M, Meaney MJ
JournalPhilos Trans R Soc Lond B Biol Sci
Volume369
Issue1652
Date Published2014 Sep 26
ISSN1471-2970
KeywordsAnimals, Blotting, Western, Chromatin Immunoprecipitation, DNA Primers, DNA-Binding Proteins, Early Growth Response Protein 1, Gene Knockdown Techniques, HEK293 Cells, Hippocampus, Humans, In Situ Hybridization, Maternal Behavior, Mutagenesis, Site-Directed, Rats, Rats, Long-Evans, Real-Time Polymerase Chain Reaction, Receptors, Glucocorticoid, Signal Transduction, Transcriptional Activation
Abstract

Variations in maternal care in the rat influence the epigenetic state and transcriptional activity of glucocorticoid receptor (GR) gene in the hippocampus. The mechanisms underlying this maternal effect remained to be defined, including the nature of the relevant maternally regulated intracellular signalling pathways. We show here that increased maternal licking/grooming (LG), which stably enhances hippocampal GR expression, paradoxically increases hippocampal expression of the methyl-CpG binding domain protein-2 (MBD2) and MBD2 binding to the exon 17 GR promoter. Knockdown experiments of MBD2 in hippocampal primary cell culture show that MBD2 is required for activation of exon 17 GR promoter. Ectopic co-expression of nerve growth factor-inducible protein A (NGFI-A) with MBD2 in HEK 293 cells with site-directed mutagenesis of the NGFI-A response element within the methylated exon 17 GR promoter supports the hypothesis that MBD2 collaborates with NGFI-A in binding and activation of this promoter. These data suggest a possible mechanism linking signalling pathways, which are activated by behavioural stimuli and activation of target genes.

DOI10.1098/rstb.2013.0513
Alternate JournalPhilos. Trans. R. Soc. Lond., B, Biol. Sci.
PubMed ID25135974
PubMed Central IDPMC4142034
Grant List / / Canadian Institutes of Health Research / Canada

  • Douglas Hospital
  • Dobell Pavillion
  • Brain imaging centre