title: The methylated-DNA binding protein MBD2 enhances NGFI-A (egr-1)-mediated transcriptional activation of the glucocorticoid receptor.
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.
authors.affiliation: Department of Psychology and Neuroscience, Dalhousie University, Life Science Research Institute, 1348 Summer Street, Halifax, Nova Scotia, Canada B3H 0A8.
authors.forename: Ian C G
authors.initials: IC
authors.lastname: Weaver
authors.affiliation: Lumder Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 LaSalle Boulevard, Montréal, Québec, Canada H4H 1R3 Sackler Program for Epigenetics and Psychobiology at McGill University, Montréal, Québec, Canada H3A 0G4.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Hellstrom
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Oslar Promenade, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Shelley E
authors.initials: SE
authors.lastname: Brown
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Oslar Promenade, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Andrews
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Oslar Promenade, Montréal, Québec, Canada H3G 1Y6.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Dymov
authors.affiliation: Lumder Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 LaSalle Boulevard, Montréal, Québec, Canada H4H 1R3 Sackler Program for Epigenetics and Psychobiology at McGill University, Montréal, Québec, Canada H3A 0G4.
authors.forename: Josie
authors.initials: J
authors.lastname: Diorio
authors.affiliation: Lumder Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 LaSalle Boulevard, Montréal, Québec, Canada H4H 1R3 Sackler Program for Epigenetics and Psychobiology at McGill University, Montréal, Québec, Canada H3A 0G4.
authors.forename: Tie-Yuan
authors.initials: TY
authors.lastname: Zhang
authors.affiliation: Sackler Program for Epigenetics and Psychobiology at McGill University, Montréal, Québec, Canada H3A 0G4 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Oslar Promenade, Montréal, Québec, Canada H3G 1Y6 moshe.szyf@mcgill.ca.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Lumder Centre for Neuroinformatics and Mental Health, Douglas Mental Health University Institute, McGill University, 6875 LaSalle Boulevard, Montréal, Québec, Canada H4H 1R3 Sackler Program for Epigenetics and Psychobiology at McGill University, Montréal, Québec, Canada H3A 0G4 michael.meaney@mcgill.ca.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Meaney
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008425:Maternal Behavior / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C115368:MBD2 protein; D011965:Receptors, Glucocorticoid
keywords: NGFI-A; glucocorticoid receptor; hippocampal neurons; maternal care; methyl-CpG binding domain protein-2; serotonin