Comparison of Glucocorticoid Receptor- and Epigenetically Regulated Genes in Proliferating Versus Growth-Arrested Neuro-2a Cells

Jurgen      Zschocke; Peter      Weber; Nicole      Zimmermann; Theo      Rein

Abstract

In recent years, it has been established that environmental stress leaves enduring traces at distinct sites on the chromatin, accompanied by permanent alterations of gene transcription. This process depends on duration and extent of the discharge of stress hormones. Here, we aimed at identifying genes that are both regulated by the glucocorticoid receptor (GR) and display epigenetic features of transcriptional control. We used neuronal Neuro-2a cells as model system; cells were transiently transfected with GR and exposed to dexamethasone (Dex) for 2 days, either under conditions of cell proliferation or after serum deprivation-induced growth arrest. In parallel, Neuro-2a cells were treated with the histone deacetylase inhibitor trichostatin A. Comparison of gene expression profiles obtained from wholegenome microarray analyses revealed a network of genes that were GR-dependent and under control of epigenetic factors. Gene set enrichment analysis was performed in order to obtain insight into functional mechanisms implicated in stress hormone physiology. Dex response varied between proliferating and growth-arrested cells; enrichment was found for genes associated with metabolic pathways in proliferating cells, and for genes linked to inflammation in growth-arrested cells. The set of genes that were regulated by Dex under both growth conditions (proliferation and arrest) as well as by trichostatin A - (under cell proliferation) was enriched in mRNA transcripts encoding proteins which play a role in development and homeostasis. In summary, this study introduces a conceptual approach and incipient proof-of-concept for the identification of candidate genes that might be epigenetically programmed by activated GR.

Keywords: Dexamethasone, gene set enrichment analysis, glucocorticoid receptor, histone, microarray.

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