Glucocorticoid-induced chromatin remodeling: A novel molecular mechanism of traumatic stress

While the actions of glucocorticoids (GCs) on brain function have been comprehensively studied, understanding of the underlying genomic mechanisms is advancing slowly. Recent evidence shows that the transcriptional activation of the GC target gene is mediated by remodeling of chromatin. Such chromatin remodeling may specifically occur in the GC receptor-regulated promoter region of the target genes. Chromatin remodeling is complex and essential in numerous cellular processes. It may play a role in response to psychological stress. In this chapter, we will review information regarding the role of chromatin remodeling in responding to traumatic stress. As an example we will discuss chromatin remodeling in GC-induced gene expression of p11, a traumatic stress-related molecule. We discuss how GC regulates the expression of p11 in an animal model and in a culture cell line. We will present the evidence showing that the ligand-activated glucocorticoid receptor (GR) interacts with two glucocorticoid response elements (GREs) in the p11 gene promoter region to up-regulate the p11. We also demonstrate that RU486, a glucocorticoid receptor antagonist, and mutation of GREs both block glucocorticoid-induced p11 over-expression, suggesting that glucocorticoid-induced p11 over-expression is mediated by GR and GREs. Thus, the p11 gene can be transcriptionally activated. We discuss the first step toward identifying chromatin modifications leading to the expression of the p11 gene in the brain of animals in rodent stressed model. A recently developed method that examines protein-DNA interactions within the context of living cells, i.e., chromatin immunoprecipitation, has been performed to study the binding of GR to DNA in brain. This method has been used to examine the dynamics of the binding of steroid receptors to DNA and the role of co-regulators in the effect of glucocorticoids on gene expression particularly in the brain. Glucocorticoid regulation of gene expression occurs via GR and the mechanisms are varied and complex. Ligand-activated GR can regulate gene expression by binding to transcription factors to trans-activate or trans-repress expression of genes that lack functional GRE cis-elements in their promoter region. Ligand-activated GR also recruits various coactivators or corepressors to the promoters of GR targeted genes, which contribute to chromatin remodeling, as does histone acetylation and deacetylation by histone deacetylases (HDAC). The characteristics of glucocorticoids indicate that their regulation of the expression of the p11 gene might be at the chromatin level. In this chapter we will discuss the possible molecular mechanism of gene regulation associated with chromatin remodeling. We translate this information into the knowledge required to examine the possibility of using a histone deacetylase inhibitor (HDACi), such as valproic acid (VPA), to treat post-traumatic disorder (PTSD). Therefore, these studies in stress-induced chromatin remodeling provide not only the information for understanding the molecular mechanisms in the glucocorticoid-mediated gene expression, but also identify a new therapeutic target, chromatin modeling, for stress related mental diseases, such as PTSD and depressive disorders.