The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes.
Maternal care alters epigenetic programming of glucocorticoid receptor (GR) gene expression in the hippocampus, and increased postnatal maternal licking/grooming (LG) behavior enhances nerve growth factor-inducible protein A (NGFI-A) transcription factor binding to the exon 1(7) GR promoter within the hippocampus of the offspring. We tested the hypothesis that NGFI-A binding to the exon 1(7) GR promoter sequence marks this sequence for histone acetylation and DNA demethylation and that such epigenetic alterations subsequently influence NGFI-A binding and GR transcription. We report that (1) NGFI-A binding to its consensus sequence is inhibited by DNA methylation, (2) NGFI-A induces the activity of exon 1(7) GR promoter in a transient reporter assay, (3) DNA methylation inhibits exon 1(7) GR promoter activity, and (4) whereas NGFI-A interaction with the methylated exon 1(7) GR promoter is reduced, NGFI-A overexpression induces histone acetylation, DNA demethylation, and activation of the exon 1(7) GR promoter in transient transfection assays. Site-directed mutagenesis assays demonstrate that NGFI-A binding to the exon 1(7) GR promoter is required for such epigenetic reprogramming. In vivo, enhanced maternal LG is associated with increased NGFI-A binding to the exon 1(7) GR promoter in the hippocampus of pups, and NGFI-A-bound exon 1(7) GR promoter is unmethylated compared with unbound exon 1(7) GR promoter. Knockdown experiments of NGFI-A in hippocampal primary cell culture show that NGFI-A is required for serotonin-induced DNA demethylation and increased exon 1(7) GR promoter expression. The data are consistent with the hypothesis that NGFI-A participates in epigenetic programming of GR expression.
Weaver
Ian C G
IC
Douglas Hospital Research Center, Montréal, Québec, Canada H4H 1R3.
D'Alessio
Ana C
AC
Brown
Shelley E
SE
Hellstrom
Ian C
IC
Dymov
Sergiy
S
Sharma
Shakti
S
Szyf
Moshe
M
Meaney
Michael J
MJ
D000818:Animals; D001522:Behavior, Animal; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D002874:Chromosome Mapping; D019175:DNA Methylation; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D044127:Epigenesis, Genetic / Q000502:physiology*; D005091:Exons / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D017781:Genes, Immediate-Early / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008425:Maternal Behavior / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D014162:Transfection / Q000379:methods
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D011965:Receptors, Glucocorticoid; D012701:Serotonin