Abstract
Glucocorticoids and their receptor (GR) have been an important area of research because of their pleiotropic physiological functions and extensive use in the clinic. In addition, the association between GR and glucocorticoids, which is highly specific, leads to rapid nuclear translocation where GR associates with chromatin to regulate gene transcription. This simplified model system has been instrumental for studying the complexity of transcription regulation processes occurring at chromatin. In this review we discuss our current understanding of GR action that has been enhanced by recent developments in genome wide measurements of chromatin accessibility, histone marks, chromatin remodeling and 3D chromatin structure in various cell types responding to glucocorticoids.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AP-1:
-
Activator protein 1
- ChIP:
-
Chromatin immunoprecipitation
- ChIP-exo:
-
ChIP combined with lambda exonuclease digestion followed by high-throughput sequencing
- ChIP-seq:
-
ChIP-sequencing
- DBD:
-
DNA-binding domain
- Dex:
-
Dexamethasone
- DHS:
-
DNase I hypersensitive site
- E2:
-
Estradiol
- ER:
-
Estrogen receptor
- GCs:
-
Glucocorticoids
- GRE:
-
Glucocorticoid response elements
- GR:
-
Glucocorticoid receptor
- GRBs:
-
GR binding sites
- nGREs:
-
Negative glucocorticoid response elements
- PTMs:
-
Post-translational modifications
- Pol II:
-
RNA polymerase II
- TADs:
-
Topologically associated domains
- TF:
-
Transcription factor
- TSS:
-
Transcription start site
- ZF:
-
Zinc finger
References
Addison T (1855) On the constitutional and local effects of disease of the supra-renal capsules, 1 ed. Samuel Highley, London
Alangari AA (2010) Genomic and non-genomic actions of glucocorticoids in asthma. Ann Thorac Med 5:133–139. doi:10.4103/1817-1737.65040
Beato M (1989) Gene regulation by steroid hormones. Cell 56:335–344. doi:10.1016/0092-8674(89)90237-7
Beato M, Herrlich P, Schütz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857. doi:10.1016/0092-8674(95)90201-5
Biddie S, John S, Sabo P et al (2011) Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 43:145–155. doi:10.1016/j.molcel.2011.06.016
Bledsoe RK, Montana VG, Stanley TB et al (2002) Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110:93–105. doi:10.1016/S0092-8674(02)00817-6
Burns CM (2016) The history of cortisone discovery and development. Rheum Dis Clin N Am 42:1–14. doi:10.1016/j.rdc.2015.08.001
Carnes M, Lent S, Feyzi J, Hazel D (1989) Plasma adrenocorticotropic hormone in the rat demonstrates three different rhythms within 24 h. Neuroendocrinology 50:17–25. doi:10.1159/000125197
Carroll JS, Meyer CA, Song J et al (2006) Genome-wide analysis of estrogen receptor binding sites. Nat Genet 38:1289–1297. doi:10.1038/ng1901
Cheung J, Smith DF (2000) Molecular chaperone interactions with steroid receptors: an update. Mol Endocrinol 14:939–946. doi:10.1210/mend.14.7.0489
Chinenov Y, Coppo M, Gupte R et al (2014) Glucocorticoid receptor coordinates transcription factor-dominated regulatory network in macrophages. BMC Genomics 15(656). doi:10.1186/1471-2164-15-656
Chung S, Son GH, Kim K (2011) Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim Biophys Acta Mol basis Dis 1812:581–591. doi:10.1016/j.bbadis.2011.02.003
Cirillo LA, Mcpherson CE, Bossard P et al (1998) Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J 17:244–254
Clapier CR, Cairns BR (2009) The biology of chromatin remodeling complexes. Annu Rev Biochem 78:273–304. doi:10.1146/annurev.biochem.77.062706.153223
Cole TJ, Blendy JA, Monaghan AP et al (1995) Molecular genetic analysis of glucocorticoid signaling during mouse development. Steroids 60:93–96
Coolens JL, Van Baelen H, Heyns W (1987) Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin. J Steroid Biochem 26:197–202
Coulon A, Chow CC, Singer RH, Larson DR (2013) Eukaryotic transcriptional dynamics: from single molecules to cell populations. Nat Rev Genet 14:572–584. doi:10.1038/nrg3484
Coutinho AE, Chapman KE (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335:2–13. doi:10.1016/j.mce.2010.04.005
Cushing H (1932) The basophil adenomas of the pitiutary body and their clinical manifestations (pituitary basophilism). Bull Johns Hopkins Hosp 50:180–181
Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR (1990) Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249(80):1266–1272
Dixon JR, Selvaraj S, Yue F et al (2012) Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485:376–380. doi:10.1038/nature11082
Freedman LP, Luisi BF, Korszun ZR et al (1988) The function and structure of the metal coordination sites within the glucocorticoid receptor DNA binding domain. Nature 334:543–546. doi:10.1038/334543a0
Glass CK, Saijo K (2010) Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol 10:365–376. doi:10.1038/nri2748
Greenstein S, Ghias K, Krett NL, Rosen ST (2002) Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin Cancer Res 8:1681–1694
Grøntved L, John S, Baek S et al (2013) C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J 32:1568–1583. doi:10.1038/emboj.2013.106
Guertin MJ, Zhang X, Coonrod SA, Hager GL (2014) Transient estrogen receptor binding and p300 redistribution support a squelching mechanism for estradiol-repressed genes. Mol Endocrinol 28:1522–1533. doi:10.1210/me.2014-1130
Hager GL, Elbi C, Johnson TA et al (2006) Chromatin dynamics and the evolution of alternate promoter states. Chromosom Res 14:107–116. doi:10.1007/s10577-006-1030-0
Hah N, Murakami S, Nagari A et al (2013) Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23:1210–1223. doi:10.1101/gr.152306.112
Hakim O, John S, Ling JQ et al (2009) Glucocorticoid receptor activation of the Ciz1-Lcn2 locus by long range interactions. J Biol Chem 284:6048–6052. doi:10.1074/jbc.C800212200
Hay D, Hughes JR, Babbs C et al (2016) Genetic dissection of the α-globin super-enhancer in vivo. Nat Genet 48:895–903. doi:10.1038/ng.3605
Herrlich P (2001) Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20:2465–2475. doi:10.1038/sj.onc.1204388
Hua G, Paulen L, Chambon P et al (2016) GR SUMOylation and formation of an SUMO-SMRT/ NCoR1-HDAC3 repressing complex is mandatory for GC-induced IR nGRE-mediated transrepression. Proc Natl Acad Sci 113(5):E626–E634. doi:10.1073/pnas.1522821113
Jiang C, Pugh BF (2009) Nucleosome positioning and gene regulation: advances through genomics. Nat Rev Genet 10:161–172. doi:10.1038/nrg2522
Jin F, Li Y, Dixon JR et al (2013) A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 503:290–294. doi:10.1038/nature12644
John S, Johnson TA, Sung M-H et al (2009) Kinetic complexity of the global response to glucocorticoid receptor action. Endocrinology 150:1766–1774. doi:10.1210/en.2008-0863
John S, Sabo PJ, Johnson TA et al (2008) Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell 29:611–624. doi:10.1016/j.molcel.2008.02.010
John S, Sabo PJ, Thurman RE et al (2011) Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 43:264–268. doi:10.1038/ng.759
Kadmiel M, Cidlowski JA (2013) Glucocorticoid receptor signaling in health and disease. Trends Pharmacol Sci 34:518–530. doi:10.1016/j.tips.2013.07.003
Kuznetsova T, Wang S-Y, Rao NA et al (2015) Glucocorticoid receptor and nuclear factor kappa-b affect three-dimensional chromatin organization. Genome Biol 16(264). doi:10.1186/s13059-015-0832-9
Langlais D, Couture C, Balsalobre A et al (2012) The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol Cell 47:38–49. doi:10.1016/j.molcel.2012.04.021
Le Dily F, Baù D, Pohl A et al (2014) Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation. Genes Dev 28:2151–2162. doi:10.1101/gad.241422.114
Le Dily F, Beato M (2015) TADs as modular and dynamic units for gene regulation by hormones. FEBS Lett 589:2885–2892. doi:10.1016/j.febslet.2015.05.026
Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128:707–719
Li Q, Wrange O (1995) Accessibility of a glucocorticoid response element in a nucleosome depends on its rotational positioning. Mol Cell Biol 15:4375–4384
Lim H-W, Uhlenhaut NH, Rauch A et al (2015) Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res 25:836–844. doi:10.1101/gr.188581.114
Lin K-T, Wang L-H (2016) New dimension of glucocorticoids in cancer treatment. Steroids 111:84–88. doi:10.1016/j.steroids.2016.02.019
Luca F, Maranville JC, Richards AL et al (2013) Genetic, functional and molecular features of glucocorticoid receptor binding. PLoS One 8:e61654. doi:10.1371/journal.pone.0061654
Luisi BF, WX X, Otwinowski Z et al (1991) Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352:497–505. doi:10.1038/352497a0
Melters DP, Nye J, Zhao H, Dalal Y (2015) Chromatin dynamics in vivo: a game of musical chairs. Genes (Basel) 6:751–776. doi:10.3390/genes6030751
Meyer ME, Gronemeyer H, Turcotte B et al (1989) Steroid hormone receptors compete for factors that mediate their enhancer function. Cell 57:433–442
Morris SA, Baek S, Sung M-H et al (2014) Overlapping chromatin-remodeling systems collaborate genome wide at dynamic chromatin transitions. Nat Struct Mol Biol 21:73–81. doi:10.1038/nsmb.2718
Nagaich AK, Walker DA, Wolford R, Hager GL (2004) Rapid periodic binding and displacement of the glucocorticoid receptor during chromatin remodeling. Mol Cell 14:163–174
Nora EP, Lajoie BR, Schulz EG et al (2012) Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485:381–385. doi:10.1038/nature11049
Ostuni R, Piccolo V, Barozzi I et al (2013) Latent enhancers activated by stimulation in differentiated cells. Cell 152:157–171. doi:10.1016/j.cell.2012.12.018
Pan D, Kocherginsky M, Conzen SD (2011) Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer. Cancer Res 71:6360–6370. doi:10.1158/0008-5472.CAN-11-0362
Polman JAE, Welten JE, Bosch DS et al (2012) A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells. BMC Neurosci 13(118). doi:10.1186/1471-2202-13-118
Presman DM, Ganguly S, Schiltz RL et al (2016) DNA binding triggers tetramerization of the glucocorticoid receptor in live cells. Proc Natl Acad Sci U S A 113:8236–8241. doi:10.1073/pnas.1606774113
Ramamoorthy S, Cidlowski JA (2013) Ligand-induced repression of the glucocorticoid receptor gene is mediated by an NCoR1 repression complex formed by long-range chromatin interactions with intragenic glucocorticoid response elements. Mol Cell Biol 33:1711–1722. doi:10.1128/MCB.01151-12
Rao NAS, McCalman MT, Moulos P et al (2011) Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res 21:1404–1416. doi:10.1101/gr.118042.110
Reddy TE, Pauli F, Sprouse RO et al (2009) Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res 19:2163–2171. doi:10.1101/gr.097022.109
Richard-Foy H, Hager GL (1987) Sequence-specific positioning of nucleosomes over the steroid-inducible MMTV promoter. EMBO J 6:2321–2328
Rogatsky I, Luecke HF, Leitman DC, Yamamoto KR (2002) Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. Proc Natl Acad Sci U S A 99:16701–16706. doi:10.1073/pnas.262671599
Roqueta-Rivera M, Esquejo RM, Phelan PE et al (2016) SETDB2 links glucocorticoid to lipid metabolism through Insig2a regulation. Cell Metab 24:474–484. doi:10.1016/j.cmet.2016.07.025
Sacta MA, Chinenov Y, Rogatsky I (2016) Glucocorticoid signaling: an update from a genomic perspective. Annu Rev Physiol 78:155–180. doi:10.1146/annurev-physiol-021115-105323
Sanyal A, Lajoie BR, Jain G, Dekker J (2012) The long-range interaction landscape of gene promoters. Nature 489:109–113. doi:10.1038/nature11279
Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55–89. doi:10.1210/edrv.21.1.0389
Sasse SK, Zuo Z, Kadiyala V et al (2015) Response element composition governs correlations between binding site affinity and transcription in glucocorticoid receptor feed-forward loops. J Biol Chem 290:19756–19769. doi:10.1074/jbc.M115.668558
Schäcke H, Döcke WD, Asadullah K (2002) Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther 96:23–43
Schiller BJ, Chodankar R, Watson LC et al (2014) Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes. Genome Biol 15(418). doi:10.1186/s13059-014-0418-y
Shin HY, Willi M, Yoo KH et al (2016) Hierarchy within the mammary STAT5-driven Wap super-enhancer. Nat Genet 48:904–911. doi:10.1038/ng.3606
Shipp LE, Lee JV, C-Y Y et al (2010) Transcriptional regulation of human dual specificity protein phosphatase 1 (DUSP1) gene by glucocorticoids. PLoS One 5:e13754. doi:10.1371/journal.pone.0013754
Shlyueva D, Stampfel G, Stark A (2014) Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev Genet 15:272–286. doi:10.1038/nrg3682
Soufi A, Donahue G, Zaret KS et al (2012) Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151:994–1004. doi:10.1016/j.cell.2012.09.045
Soufi A, Garcia MF, Jaroszewicz A et al (2015) Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell 161:555–568. doi:10.1016/j.cell.2015.03.017
Stahn C, Buttgereit F (2008) Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol 4:525–533. doi:10.1038/ncprheum0898
Starick SR, Ibn-Salem J, Jurk M et al (2015) ChIP-exo signal associated with DNA-binding motifs provide insights into the genomic binding of the glucocorticoid receptor and cooperating transcription factors. Genome Res 25:825–835. doi:10.1101/gr.185157.114
Stavreva DA, Coulon A, Baek S et al (2015) Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing. Genome Res 25:845–857. doi:10.1101/gr.184168.114
Stavreva DA, Wiench M, John S et al (2009) Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat Cell Biol 11:1093–1102. doi:10.1038/ncb1922
Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45. doi:10.1038/47412
Surjit M, Ganti KP, Mukherji A et al (2011) Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145:224–241. doi:10.1016/j.cell.2011.03.027
Swinstead EE, Miranda TB, Paakinaho V et al (2016a) Steroid Receptors Reprogram FoxA1 Occupancy through Dynamic Chromatin Transitions. Cell 165:593–605. doi:10.1016/j.cell.2016.02.067
Swinstead EE, Paakinaho V, Presman DM, Hager GL (2016b) Pioneer factors and ATP-dependent chromatin remodeling factors interact dynamically: a new perspective: multiple transcription factors can effect chromatin pioneer functions through dynamic interactions with ATP-dependent chromatin remodeling factors. BioEssays 38:1150–1157. doi:10.1002/bies.201600137
Thurman RE, Rynes E, Humbert R et al (2012) The accessible chromatin landscape of the human genome. Nature 489:75–82. doi:10.1038/nature11232
Uhlenhaut NH, Barish GD, RT Y et al (2013) Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol Cell 49:158–171. doi:10.1016/j.molcel.2012.10.013
van der Laan S, de Kloet ER, Meijer OC (2009) Timing is critical for effective glucocorticoid receptor mediated repression of the cAMP-induced CRH gene. PLoS One 4:e4327. doi:10.1371/journal.pone.0004327
Vandevyver S, Dejager L, Libert C (2012) On the trail of the glucocorticoid receptor: into the nucleus and back. Traffic 13:364–374. doi:10.1111/j.1600-0854.2011.01288.x
Vockley CM, D’Ippolito AM, McDowell IC et al (2016) Direct GR binding sites potentiate clusters of TF binding across the human genome. Cell 166:1269–1281. doi:10.1016/j.cell.2016.07.049
Voss TC, John S, Hager GL (2006) Single-cell analysis of glucocorticoid receptor action reveals that stochastic post-chromatin association mechanisms regulate ligand-specific transcription. MolEndocrinol 20:2641–2655
Voss TC, Schiltz RL, Sung M-H et al (2011) Dynamic exchange at regulatory elements during chromatin remodeling underlies assisted loading mechanism. Cell 146:544–554. doi:10.1016/j.cell.2011.07.006
Voss TC, Schiltz RL, Sung M-H et al (2009) Combinatorial probabilistic chromatin interactions produce transcriptional heterogeneity. J Cell Sci 122:345–356. doi:10.1242/jcs.035865
Weinberger C, Hollenberg SM, Rosenfeld MG, Evans RM (1985) Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product. Nature 318:670–672
Wiench M, John S, Baek S et al (2011) DNA methylation status predicts cell type-specific enhancer activity. EMBO J 30:3028–3039. doi:10.1038/emboj.2011.210
Young EA, Abelson J, Lightman SL (2004) Cortisol pulsatility and its role in stress regulation and health. Front Neuroendocr 25:69–76. doi:10.1016/j.yfrne.2004.07.001
Yu C-Y, Mayba O, Lee JV et al (2010) Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLoS One 5:e15188. doi:10.1371/journal.pone.0015188
Zaret KS, Carroll JS (2011) Pioneer transcription factors: establishing competence for gene expression. Genes Dev 25:2227–2241. doi:10.1101/gad.176826.111
Zaret KS, Yamamoto KR (1984) Reversible and persistent changes in chromatin structure accompany activation of a glucocorticoid-dependent enhancer element. Cell 38:29–38
Zen M, Canova M, Campana C et al (2011) The kaleidoscope of glucorticoid effects on immune system. Autoimmun Rev 10:305–310. doi:10.1016/j.autrev.2010.11.009
Zhang X, Choi PS, Francis JM et al (2015) Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers. Nat Genet 48:1–8. doi:10.1038/ng.3470
Acknowledgements
We apologize to those authors whose articles we have not cited due to space constraints. This work is supported by the Israel Science Foundation (grant 748/14), Marie Curie Integration grant (CIG)- FP7-PEOPLE-20013-CIG-618763, the United States-Israel Bi-national Science Foundation (BSF) and I-CORE Program of the Planning and Budgeting Committee, and The Israel Science Foundation grant no. 41/11.
Author information
Authors and Affiliations
Corresponding author
Additional information
Handling Editor: Reimer Stick
Electronic supplementary material
ESM 1
(DOCX 56 kb)
Rights and permissions
About this article
Cite this article
Grbesa, I., Hakim, O. Genomic effects of glucocorticoids. Protoplasma 254, 1175–1185 (2017). https://doi.org/10.1007/s00709-016-1063-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00709-016-1063-y