The Transcription Factor Nerve Growth Factor-Inducible Protein A Mediates Epigenetic Programming: Altering Epigenetic Marks by Immediate-Early Genes

TLDR

Maternal licking/grooming enhances NGFI‑A binding to the exon 1 7 glucocorticoid receptor promoter in offspring hippocampus, linking maternal care to epigenetic regulation of GR expression. The study tested whether NGFI‑A binding marks the exon 1 7 GR promoter for histone acetylation and DNA demethylation, thereby influencing NGFI‑A recruitment and GR transcription. NGFI‑A binding is inhibited by DNA methylation but, when overexpressed, induces histone acetylation, DNA demethylation, and promoter activation; in vivo maternal licking/grooming increases NGFI‑A binding and unmethylated promoter, while NGFI‑A knockdown blocks serotonin‑induced demethylation and GR up‑regulation, confirming NGFI‑A’s role in epigenetic programming of GR.

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.