Chromatin architecture defines the glucocorticoid response
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.
Section snippets
The whole genome as a model system
The development of microarray technology altered the methodology of nuclear receptor research away from model promoters. This progression has only been strengthened with the advent of next-generation sequencing. Moving from model promoters to all promoters has changed the perspective in which we view transcriptional initiation. The initial work performed with tiled microarrays looking at nuclear receptor recruitment immediately altered the paradigm as the majority of binding sites were not
Chromatin is a determinate in GR recruitment
With the global cistrome of GR binding being defined now in several systems, the key mechanisms directing GR recruitment have been investigated. While the vast majority of binding sites (62–80%) contain sequences considered to be a classical GRE, it is clear the GR can be located at other regions either by tethering or through alternate recognition motifs (So et al., 2007, Reddy et al., 2009, John et al., 2011). Recent work has tried to define the molecular characteristics of true recruitment
Pioneering factors and master regulators
The role chromatin plays in defining the cellular response that a transcription factor has in a given cell type has led to an investigation into the mechanisms by which these underlying tracks of specificity are laid. The identification of FOXA1 as a critical regulator of estrogen receptor action reintroduced the idea of pioneering factors (Carroll et al., 2006, Lupien et al., 2008, Eeckhoute et al., 2006). The idea of master regulators defining the cell specificity of transcription factors is
Chromatin remodeling complexes
There is quite a body of research detailing the requirement of chromatin remodeling complexes, most notably SWI/SNF, in nuclear receptor and GR mediated gene transactivation (Fryer and Archer, 1998, Trotter and Archer, 2007). The core subunits of the SWI/SNF complex, either Brg1 or Brm, are able to utilize the energy from ATP hydrolysis to functionally reorder chromatin structure (Kwon et al., 1994). During GR activation, the complex is recruited to remodel chromatin structure and facilitates
Chromatin characterization of GR binding loci
The recent work has demonstrated that GR binding regions usually maintain an accessible state prior to receptor binding. It is less clear what that accessibility represents in terms of physical chromatin structure and nucleosome makeup. The human genome encodes for several variants of the histone proteins each of which can be extensively posttranslationally modified (review in (Campos and Reinberg, 2009)). The initial work characterizing recruitment sites in detail has only begun to
Concluding remarks
The importance of chromatin in dictating transcription factor actions is apparent, but the mechanisms of control are only beginning to be understood. Prior accessibility of the recruitment site correlates strongly with binding events in the presence of hormone and the role of pioneering factors in laying the tracks of that accessibility is becoming clearer. Yet, we still don’t understand the coordination of these factors to dictate cell type specificity. This control is clearly maintained by a
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2017, Journal of Biological ChemistryCitation Excerpt :Our results indicate that the increased accessibility of GBRs induced by dexamethasone requires gene-specific chromatin remodelers, and the dexamethasone dependence of the chromatin transition indicates a requirement for GR to recruit or activate the chromatin remodelers, thus supporting our conclusion that GR occupancy and chromatin remodeling are co-dependent processes. Also consistent with this is the previous demonstration that components of the Swi-Snf chromatin remodeling complex (for which BRG1 and BRM serve as alternative ATPase subunits) interact directly with GR and are recruited to many GBRs in a hormone-induced manner (22–24, 27). In addition, BRM and GR have been shown previously to regulate the occupancy of each other on GBRs in a gene-specific manner (27).