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Genes are not simply turned on or off, but instead their expression is fine-tuned to meet the needs of a cell. How genes are modulated so precisely is not well understood. The glucocorticoid receptor (GR) regulates target genes by associating with specific DNA binding sites, the sequences of which differ between genes. Traditionally, these binding sites(More)
The acetylation state of histones plays a central role in determining gene expression in chromatin. The reestablishment of the acetylation state of nucleosomes after DNA replication and chromatin assembly requires both deacetylation and acetylation of specific lysine residues on newly incorporated histones. In this study, the MYST family acetyltransferase(More)
Upon binding of cortisol, the glucocorticoid receptor (GR) regulates the transcription of specific target genes, including those that encode the stress hormones corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone. Dysregulation of the stress axis is a hallmark of major depression in human patients. However, it is still unclear how(More)
Cancer cachexia is a complex syndrome which occurs in more than two-thirds of patients who die with advanced cancer. The main components of this pathological state are anorexia and metabolic abnormalities such as glucose intolerance, fat depletion, and muscle protein catabolism among others. The aim of the present study is to review the different(More)
The classical DNA recognition sequence of the glucocorticoid receptor (GR) appears to be present at only a fraction of bound genomic regions. To identify sequences responsible for recruitment of this transcription factor (TF) to individual loci, we turned to the high-resolution ChIP-exo approach. We exploited this signal by determining footprint profiles of(More)
Isogenic settings are routine in model organisms, yet remain elusive for genetic experiments on human cells. We describe the use of designed zinc finger nucleases (ZFNs) for efficient transgenesis without drug selection into the PPP1R12C gene, a "safe harbor" locus known as AAVS1. ZFNs enable targeted transgenesis at a frequency of up to 15% following(More)
One fascinating aspect of glucocorticoid signaling is their broad range of physiological and pharmacological effects. These effects are at least in part a consequence of transcriptional regulation by the glucocorticoid receptor (GR). Activation of GR by glucocorticoids results in tissue-specific changes in gene expression levels with some genes being(More)
Incubation of rat isolated skeletal muscles (extensor digitorum longus) in the presence of 100 ng/ml of human recombinant interleukin-15 (IL-15) resulted in a significant decrease in total proteolytic rate, while it had no effect on total protein synthesis as measured by the incorporation of (14)C-phenylalanine into muscle protein. In addition, IL-15 had no(More)
In addition to guiding proteins to defined genomic loci, DNA can act as an allosteric ligand that influences protein structure and activity. Here we compared genome-wide binding, transcriptional regulation, and, using NMR, the conformation of two glucocorticoid receptor (GR) isoforms that differ by a single amino acid insertion in the lever arm, a domain(More)
The activities of intracellular receptors are regulated by their cognate ligands. Here we show that a series of related arylpyrazole compounds, which specifically bind the glucocorticoid receptor (GR), selectively modulated GR-regulated biological functions in preadipocyte, pre-osteoblast, and lung epithelial cell lines. Indeed, when we monitored 17(More)