Glucocorticoid receptor (GR), the founding member of the nuclear receptor superfamily, is a ubiquitously expressed, ligand-regulated vertebrate transcriptional regulatory factor (TRF) that regulates precisely determined gene networks.
Although precise, GR-regulated gene networks are highly plastic, changing dramatically with changes in cell or physiological context.
GR is regulated by multiple signals (ligands, DNA-binding sequences, post-translational modifications and non-GR TRFs). We propose that each of these signals acts as an allosteric effector that conveys gene, cell or physiological context information to GR by specifically altering its conformation.
Integrated signal-driven conformational modifications of GR produce context-specific patterns of GR protein surfaces that are recognized by unique combinations of co-regulator proteins.
GR, and perhaps many or all other TRFs, seems to lack intrinsic transcription regulatory activity and instead may be a molecular scaffold whose signal-driven structures nucleate the assembly of enzymatic machineries that confer distinct regulatory outcomes.
Regulatory precision, signal-driven allostery and context-specified network plasticity are properties that are likely shared by most, if not all, metazoan TRFs.
The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniquely determined by particular cellular and physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity. This structural and mechanistic perspective on GR regulatory specificity is likely to extend to other eukaryotic TRFs.
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The authors thank the members of the Yamamoto laboratory for critical reading of the manuscript, with special note to Elaine Kirschke for insightful discussions, Samantha Cooper, Sheng-Hong Chen and Benjamin Schiller for use of unpublished data, and Kirk Ehmsen for use of unpublished data and assistance with Figure 3. E.R.W. is supported by US National Institutes of Health (NIH) predoctoral National Research Service Award (NRSA) 1G31GM113397-01A1 from the National Institute of General Medical Sciences. M.T.K. is supported by NIH postdoctoral NRSA 5T32HL007731-20 from the National Heart, Lung, and Blood Institute and by NIH grant R01CA020535 from the National Cancer Institute. E.A.O. is supported by NIH grant R01DK095750 from the National Institute of Diabetes and Digestive and Kidney Diseases, by American Heart Association (AHA) grant 14GRNT20460124 and by a W.M. Keck Foundation Medical Research Grant. K.R.Y. is supported by NIH grants R01CA020535 from the National Cancer Institute and R21ES026068 from the National Institute of Environmental Health Sciences, and by grant MCB-1615826 from the National Science Foundation.
The authors declare no competing financial interests.
- Transcriptional regulatory factors
(TRFs). A general class of sequence-specific DNA-binding proteins that regulate transcription (for example, glucocorticoid receptor).
- Nuclear receptor
A member of a superfamily of potentially ligand-gated DNA-binding transcriptional regulatory factors.
A natural hormone that binds to glucocorticoid receptor, or a synthetic derivative with physiological effects similar to the natural hormone, cortisol.
A synthetic glucocorticoid receptor (GR) ligand, developed in 1957, which is GR specific, unlike cortisol (the natural ligand), which also binds to mineralocorticoid receptor with high affinity. Dexamethasone is universally used clinically as an anti- inflammatory agent and immunosuppressant.
Inactive glucocorticoid receptor (GR) protein in a ligand-unbound state.
- Glucocorticoid response elements
(GREs). Genomic DNA segments (typically 0.5–2 kb long) that confer a specific glucocorticoid receptor response in particular contexts in vivo. The term 'response element' is appropriately unbiased with respect to potential activation ('enhancement') or repression of target gene transcription.
Conformational changes in one region of a molecule (usually a protein) that alter its function and are induced by binding of a modulator to a different, remote site on the target molecule.
- GR-binding sequence
(GBS). A short DNA sequence motif bound specifically and with high affinity by glucocorticoid receptor in vitro.
- Nuclear magnetic resonance
(NMR). A technique that uses the magnetic properties of atomic nuclei to probe chemical environments experienced by atoms, for example, within a small molecule, protein or protein–DNA complex. See Supplementary information S1 (table).
- 3-Keto steroid receptors
Members of nuclear receptor subfamily 3 (NR3), including the glucocorticoid receptor (encoded by NR3 group C member 1 (NR3C1)), mineralocorticoid receptor (encoded by NR3C2), progesterone receptor (encoded by NR3C3) and androgen receptor (encoded by NR3C4).
- Epistatic mutations
Gene alterations that display a phenotype only in the context of another mutation.
- Chromatin immunoprecipitation followed by sequencing
(ChIP-Seq). A technique to identify genomic segments occupied genome-wide in vivo by a particular antigen surface, such as a transcriptional regulatory factor epitope. See Supplementary information S1 (table).
- GR-occupied regions
(GORs). Genomic DNA segments occupied by glucocorticoid receptor (GR) in particular contexts in vivo. GOR terminology, typically identified by chromatin immunoprecipitation (ChIP), improves on the previously used GR-binding region (GBR or GRBR) nomenclature, which implies direct DNA binding rather than a broader proximity to DNA, the parameter measured by ChIP.
- DNase I-hypersensitive sites
(DHSs). Short genomic regions that are cleaved by brief exposure to low concentrations of DNase I in permeabilized cells or isolated nuclei. See Supplementary information S1 (table).
- Negative regulatory DNA sequence
(NRS). A short DNA sequence motif, under-represented at glucocorticoid receptor (GR)-occupied regions within the genome, that interferes with the ability of GR to functionally interact with DNA proximal to the motif.
- Molecular dynamics simulations
A computer simulation method to model the physical movements of atoms within a macromolecule that occur over short, fixed time intervals, giving information about dynamics within a macromolecule. See Supplementary information S1 (table).
A synthetic glucocorticoid receptor (GR) ligand, developed in 1980, which also has high affinity for progesterone receptor. As a non-standard ligand, binding of RU-486 results in both an altered GR conformation and a distinct pattern of transcription regulation compared to binding of standard glucocorticoids, such as dexamethasone and cortisol.
- Selective GR modulators
(SGRMs). Glucocorticoid receptor (GR) ligands with a regulatory range distinct from that of the standard glucocorticoid ligands cortisol and dexamethasone.
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Weikum, E., Knuesel, M., Ortlund, E. et al. Glucocorticoid receptor control of transcription: precision and plasticity via allostery. Nat Rev Mol Cell Biol 18, 159–174 (2017). https://doi.org/10.1038/nrm.2016.152