Early stress evokes dysregulation of histone modifiers in the medial prefrontal cortex across the life span

Dev Psychobiol. 2016 Mar;58(2):198-210. doi: 10.1002/dev.21365. Epub 2015 Sep 23.


Early stress has been hypothesized to recruit epigenetic mechanisms to mediate persistent molecular, cellular, and behavioral changes. Here, we have examined the consequence of the early life stress of maternal separation (ES) on the gene expression of several histone modifiers that regulate histone acetylation and methylation within the medial prefrontal cortex (mPFC), a key limbic brain region that regulates stress responses and mood-related behavior. ES animals exhibit gene regulation of both writer (histone acetyltransferases and histone methyltransferases) and eraser (histone deacetylases and histone lysine demethylases) classes of histone modifiers. While specific histone modifiers (Kat2a, Smyd3, and Suv420h1) and the sirtuin, Sirt4 were downregulated across life within the mPFC of ES animals, namely at postnatal Day 21, 2 months, and 15 months of age, we also observed gene regulation restricted to these specific time points. Despite the decline noted in expression of several histone modifiers within the mPFC following ES, this was not accompanied by any change in global or residue-specific H3 acetylation and methylation. Our findings indicate that ES results in the regulation of several histone modifiers within the mPFC across life, and suggest that such perturbations may contribute to the altered prefrontal structural and functional plasticity observed following early adversity.

Keywords: histone acetyltransferase; histone deacetylase; histone demethylase; histone methyltransferase; maternal separation; sirtuin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Blotting, Western
  • Down-Regulation
  • Epigenesis, Genetic
  • Gene Expression Regulation, Developmental / genetics*
  • Histone Acetyltransferases / genetics*
  • Histone Acetyltransferases / metabolism
  • Histone Code / genetics
  • Histone Deacetylases / genetics*
  • Histone Deacetylases / metabolism
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Male
  • Maternal Deprivation*
  • Methylation
  • Prefrontal Cortex / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sirtuins / genetics*
  • Sirtuins / metabolism
  • Stress, Psychological / genetics*
  • Stress, Psychological / metabolism


  • Histone-Lysine N-Methyltransferase
  • Histone Acetyltransferases
  • Sirtuins
  • Histone Deacetylases