Chromatin architecture defines the glucocorticoid response

Highlights

• Glucocorticoid receptor binding sites have a distinct chromatin architecture.

• Preset chromatin accessibility defines specificity.

• Glucocorticoid receptor relies on pioneer factors to preset binding sites.

Abstract

The glucocorticoid receptor (GR) functions to regulate a wide group of physiological processes through hormone inducible interaction with genomic loci and subsequent manipulation of the transcriptional output of target genes. Despite expression in a wide variety of tissues, the GR has diverse roles that are regulated tightly in a cell type specific manner. With the advent of whole genome approaches, the details of that diversity and the mechanisms regulating them are beginning to be elucidated. This review aims describe the recent advances detailing the role chromatin structure plays in dictating GR specificity.

Introduction

The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily of transcription factors that functions to control a wide array of physiological processes including proliferation, development, inflammation, and metabolic homeostasis (Sapolsky et al., 2000). Once activated by ligand, the receptor translocates to the nucleus and dimerizes on sequence specific response elements (GREs) (Mangelsdorf et al., 1995). The receptor is able recruit accessory molecules that aid in preparing the target gene for transcriptional activation or repression (Lonard and O’Malley, 2012). Many of these accessory molecules, also termed co-regulators, act to modify the chromatin structure at the response element and within the promoter of target genes (Trotter and Archer, 2008, Wolf et al., 2008). It has become abundantly clear that biology uses that chromatin structure and the ability to modify it as an important step in regulating transcription factor function (Robyr and Wolffe, 1998).

DNA in eukaryotes is packaged into nucleosomes that act as the basic units of chromatin. Each nucleosome is made up of roughly 146 bp of DNA wrapped around a histone octamer containing two copies of histones H2A, H2B, H3, and H4 (Luger et al., 1997). These nucleosomes are connected in an array by spans of linker DNA associated with histone H1 (Happel and Doenecke, 2009). The abundance of the histone H1 within this linker region has an important role in maintaining nucleosome positioning as well as defining the higher order structure of chromatin (Pennings et al., 1994, Bednar et al., 1998). Both of these functions are critical to regulating transcription factor activity. The higher order chromatin structure can be manipulated from completely open or accessible in the “beads on a string” 10 nm fiber conformation to a closed or inaccessible structure (Vaquero et al., 2003). The accessibility of the chromatin acts as a critical regulator of DNA-protein interactions (Li and Reinberg, 2011).

The role of chromatin in GR mediated transactivation has been intensely studied for many years using a number of model promoters, such as MMTV. Using these exogenous promoters, a model of GR activation has evolved in which the activated receptor acts to reorganize the chromatin architecture from an inactive to active state. The MMTV promoter, when introduced into a eukaryotic genome, assembles into an ordered array of nucleosomes (Richard-Foy and Hager, 1987). Recruitment of the receptor results in a number of changes in the chromatin structure. Most notably, the position of the nucleosome surrounding the GRE is altered increasing the accessibility of the promoter (Richard-Foy and Hager, 1987, Pina et al., 1990). This allows stable binding of other factors, such as NF-1 and Oct-1 which aid to regulate transcriptional output (Archer et al., 1991, Bruggemeier et al., 1991, Hebbar and Archer, 2007, Eisfeld et al., 1997). In this sense, the GR acts as a pioneering factor to aid other transcription factor binding. Together, a model was generated in which responsive regions are held in an inactive and inaccessible state that is remodeled by recruitment of GR and its accessory proteins to a transcriptionally permissive state. This review aims to update this model from recent work and novel technologies that have changed the perspective of GR and other nuclear receptor activities.