Epigenetic Mechanisms of the Glucocorticoid Receptor

Post-translational modification of epigenetic effectors regulates dyadic ligand-dependent glucocorticoid receptor transcriptional changes. Noncoding RNAs regulate glucocorticoid receptor expression and function. Tissue- and cell type-specific effects of glucocorticoids are conferred by chromatin-modifying and chromatin-state responsive protein interaction with the glucocorticoid receptor. The glucocorticoid receptor (GR) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. Ligand-dependent transcriptional changes induced by GR are observed across numerous tissues. However, the mechanisms by which GR achieves cell and tissue-specific effects are less clear. Epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. GR functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. Here, we describe GR interactions with these effectors and how GR acts to reshape the epigenetic landscape in response to the environment. The glucocorticoid receptor (GR) has been shown to be important for mediating cellular responses to stress and circulating glucocorticoids. Ligand-dependent transcriptional changes induced by GR are observed across numerous tissues. However, the mechanisms by which GR achieves cell and tissue-specific effects are less clear. Epigenetic mechanisms have been proposed to explain some of these differences as well as some of the lasting, even transgenerational, effects of stress and glucocorticoid action. GR functions in tandem with epigenetic cellular machinery to coordinate transcription and shape chromatin structure. Here, we describe GR interactions with these effectors and how GR acts to reshape the epigenetic landscape in response to the environment. ALL1-Fused Gene from Chromosome 9 Protein, binds histone H3 acetylated at Lys-9 (H3K9ac). Anti-Silencing Function 1A Histone Chaperone, a key component of the histone donor complex that functions in nucleosome assembly. ASH1-Like Histone Lysine Methyltransferase, methylates Lys-36 of histone H3 (H3K36me). Activating Transcription Factor 2, transcription factor that forms a complex with c-Jun and stimulates cyclic AMP responsive element (CRE)-dependent transcription, acetylates histone H2B and H4 subunits. CREB Binding Protein, transcriptional enhancer that binds to cyclic AMP binding protein, histone acetyltransferase. DNA Methyltransferase 1 Associated Protein 1, interacts with HDAC2 and may help to facilitate histone deacetylation. DNA Methyltransferase 1, transfers methyl groups to cytosine nucleotides of genomic DNA, responsible for maintaining methylation pattern during replication. DNA Methyltransferase 3 Alpha/Beta, DNA methyltransferase implicated in embryonic development, imprinting, and X-inactivation. murine homology of human Dot1L, methylates Lys-79 of histone H3 (H3K79me). epithelial Na+ channel subunit, essential role in salt retention. Enhancer of Zeste 2 Polycomb Repressive Complex 2 subunit, methylates H3K9 and H3K27. euchromatic histone lysine methyltransferase 2, methylates histone H3 at Lys-9 (H3K9me1/H3K9me2). Growth Arrest Specific 5, noncoding RNA upregulated in growth arrested cells and contains a pseudo-mimic GRE. G9a-Like Protein, methylates histone H3 at H3K9 (H3K9me1/H3K9me2). Glucocorticoid Receptor-Interacting Protein-1, transcriptional coactivator protein with histone acetyltransferase activity. Histone Deacetylase 1/2, deacetylates N terminal region of core histones. Histone Deactylase 6, deacetylates N terminal region of core histones, regulates HSP90 activity. Histone Cluster 1 H3 Family Member F, a replication-dependent histone H3-isoform. heterochromatin protein 1 gamma, binds to histone H3 methylated at Lys-9 facilitating epigenetic repression. heat shock protein 90, chaperone protein that complexes with unliganded steroid hormone receptors and regulates steroid hormone nuclear translocation. Jumonji Domain Containing 3, histone demethylase that demethylates histone H3 at H3K27. Lysine Demethylase 1A, histone demethylase that demethylates histone H3 at H3K4 and H3K9. Methyl CpG Binding Protein 2, binds to genomic methylated cytosine nucleotides. Mixed-Lineage Leukemia Protein 3, histone methyltransferase methylates histone H3 at Lys-4 (H3K4me), indispensable at promoters for GR-dependent induction of bile transporter related genes. neural precursor cell expressed, developmentally downregulated 4; E3 ubiquitin-ligase. E1A Binding Protein P300, histone acetyltransferase in complex with CREB-Binding Protein (CBP). P300/CBP-Associated Factor, acetylates histone H3 and H4 subunits. SET Domain Bifurcated 2, histone methyltransferase that tri-methylates H3K9. serum glucose kinase 1, protein-kinase induced by glucocorticoids. sirtuin 1, deacetylates H3K9ac. steroid receptor coactivator 1, histone acetyltransferase with nuclear receptor interacting domains. suppressor of variegation 3-9 homology 2, trimethylates Lys-9 of histone H3 (H3K9me3). Thymine DNA Glycosylase, binds to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) to facilitate DNA demethylation. Ten-Eleven Translocation 1, catalyzes the conversion of 5-methyl cytosine to 5-hydroxymethylcytosine (5hmC) mediating the conversion of 5hmC to 5fC. Tat Interacting Protein, 60 kDa, histone acetyltransferase that acetylates histone H4 and H2A subunits.