The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes

J Neurosci. 2007 Feb 14;27(7):1756-68. doi: 10.1523/JNEUROSCI.4164-06.2007.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Cells, Cultured
  • Chromatin Immunoprecipitation / methods
  • Chromosome Mapping
  • DNA Methylation
  • Early Growth Response Protein 1 / metabolism*
  • Electrophoretic Mobility Shift Assay / methods
  • Embryo, Mammalian
  • Epigenesis, Genetic / physiology*
  • Exons / physiology
  • Female
  • Gene Expression Regulation / physiology*
  • Genes, Immediate-Early / physiology*
  • Hippocampus / metabolism
  • Humans
  • Male
  • Maternal Behavior / physiology
  • Promoter Regions, Genetic / physiology
  • Protein Binding / physiology
  • Rats
  • Rats, Long-Evans
  • Receptors, Glucocorticoid / metabolism
  • Serotonin / metabolism
  • Transfection / methods

Substances

  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • Receptors, Glucocorticoid
  • Serotonin