RT Journal Article SR Electronic T1 The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1756 OP 1768 DO 10.1523/JNEUROSCI.4164-06.2007 VO 27 IS 7 A1 Ian C. G. Weaver A1 Ana C. D'Alessio A1 Shelley E. Brown A1 Ian C. Hellstrom A1 Sergiy Dymov A1 Shakti Sharma A1 Moshe Szyf A1 Michael J. Meaney YR 2007 UL http://www.jneurosci.org/content/27/7/1756.abstract AB 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 17 GR promoter within the hippocampus of the offspring. We tested the hypothesis that NGFI-A binding to the exon 17 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 17 GR promoter in a transient reporter assay, (3) DNA methylation inhibits exon 17 GR promoter activity, and (4) whereas NGFI-A interaction with the methylated exon 17 GR promoter is reduced, NGFI-A overexpression induces histone acetylation, DNA demethylation, and activation of the exon 17 GR promoter in transient transfection assays. Site-directed mutagenesis assays demonstrate that NGFI-A binding to the exon 17 GR promoter is required for such epigenetic reprogramming. In vivo, enhanced maternal LG is associated with increased NGFI-A binding to the exon 17 GR promoter in the hippocampus of pups, and NGFI-A-bound exon 17 GR promoter is unmethylated compared with unbound exon 17 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 17 GR promoter expression. The data are consistent with the hypothesis that NGFI-A participates in epigenetic programming of GR expression.