Cancer Res 2013 Aug 15;73(16):5130-5139

Reprogramming the chromatin landscape: interplay of the estrogen and glucocorticoid receptors at the genomic level.

Miranda TB, Voss TC, Sung MH, Baek S, John S, Hawkins M, Grøntved L, Schiltz RL, Hager GL

Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892, USA.



Crosstalk between estrogen (ER) and glucocorticoid (GR) receptors has been shown to contribute to the development and progression of breast cancer.  Importantly, the ER and GR status in breast cancer cells is a significant factor in determining the outcome of the disease.  However, mechanistic details defining the cellular interactions between ER and GR are poorly understood.  We investigated genome-wide binding profiles for ER and GR upon co-activation, and characterized status of the chromatin landscape.  We describe a novel mechanism dictating the molecular interplay between ER and GR.  Upon induction, GR modulates access of ER to specific sites in the genome by reorganization of the chromatin configuration for these elements.  Binding to these newly accessible sites occurs either by direct recognition of ER response elements, or indirectly through interactions with other factors.  The unveiling of this mechanism is important for understanding cellular interactions between ER and GR, and may represent a general mechanism for crosstalk between nuclear receptors in human disease.




Steroid receptors are a class of ligand-inducible transcription factors that control a wide spectrum of physiological processes, including metabolism, development, and inflammatory responses.  When activated by hormones, steroid receptors bind to response elements within the DNA and regulate transcription.  Both the estrogen (ER) and progesterone (PR) steroid receptors have well established roles in the development and progression of breast cancer.   However, recent evidence suggests that the glucocorticoid receptor (GR) is also an important factor in the patho-physiological progression of cancers developing from the breast (1;2).

Treatment of cells with corticosteroids and estrogen, which induce GR and ER respectively, can cause distinct physiological effects from treatment of cells with either type of hormone alone (3-6).  This suggests that there may be complex interactions between these receptors in a physiological context in which cells are exposed to multiple hormones at the same time.  However, most studies of steroid-regulated transcription are conducted in controlled environments where only one receptor is activated.  Miranda et al investigated the activities of ER and GR in the presence of both dexamethasone (Dex) and estradiol (E2) in order to determine mechanistically how ER and GR modulate each other’s functions.

Upon examining receptor binding across the genome after treatment of cells with Dex, E2, or Dex+E2, the authors observed nine different binding clusters.  In addition to the ER and GR binding events observed with activation by their corresponding hormones, Miranda et al also observed binding sites for both ER and GR that were specific to the dual hormone treatments.  This suggests the ER and GR can modulate each other’s binding specificity through a mechanism known as assisted-loading.  It has been previously shown that the access of transcription factors to genomic binding sites in cells is controlled by chromatin structure (7).  Therefore, the investigators examined the change in chromatin accessibility at these assisted-loading sites and observed an increase in DNaseI hypersensitivity within these elements.  However, there was no change in accessibility at sites where ER and GR were recruited upon activation by their corresponding hormones.  This suggests that both ER and GR can facilitate changes in chromatin structure, which allows for the recruitment of the other factor.  This change in binding of ER and GR correlates with changes in gene expression.

Further investigation of the ER assisted-loading sites revealed that ER recruitment to these sites was not dependent on the ability of ER to bind directly to the DNA.  Instead, ER’s recruitment to these sites was dependent upon AP1.  This data supports a model where co-treatment of cells activates GR, which facilitates remodeling of chromatin at specific sites within the genome.  Other factors, like AP1, then recruit ER to these sites.  In addition, ER can also induce changes in chromatin structure, which facilitates GR binding at specific genomic sites.  The outcomes of these studies are important due to the use of corticosteroids to suppress inflammation during the treatment of cancer.



Figure: Modulation of ER and GR activity by reprogramming the genome; A new mechanism governing transcription factor access in cancer development and progression. Nuclear receptors must reorganize local nucleosome structures to recognize and bind to their response elements in chromatin.  For a given receptor, a small minority of potential binding elements are available for unimpeded binding (a, c, d).  Most binding sites, however, are blocked for direct receptor interaction (b, e, f).  At a subset of elements, the action of one receptor can dramatically modulate access of an alternate factor; (g) ER acts to open a site previously closed to GR (b), so that GR can now bind.  Similarly, at site (h) GR modulates chromatin to allow binding at a site normally closed to ER (e).  GR chromatin opening can also induce binding of secondary factors, such as AP-1, allowing tethering of ER to the newly loaded factor (j).  Access for a given factor can also be reduced by modification of the local chromatin domain (i).


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