Altered expression of circadian clock genes in polyglandular autoimmune syndrome type III
Circadian timing system is a highly conserved, ubiquitous molecular “clock” which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PAS type III).
Nineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence.
There were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (Rpm/am) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (Fpm/am) was positively correlated with GILZ mRNA circadian pattern (Rpm/am) in the patient group and with the GR-a mRNA (Rpm/am) in the control group.
Our findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease.
KeywordsPolyglandular syndrome Clock genes GR-a BMAL1 PER CLOCK
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 5.D.A. Stavreva, M. Wiench, S. John, B.L. Conway-Campbell, M.A. McKenna, J.R. Pooley, T.A. Johnson, T.C. Voss, S.L. Lightman, G.L. Hager, Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription. Nat. Cell. Biol. 11, 1093–1102 (2009)CrossRefPubMedGoogle Scholar
- 8.N.C. Nicolaides, E. Charmandari, G.P. Chrousos, T. Kino, Recent advances in the molecular mechanisms determining tissue sensitivity to glucocorticoids: novel mutations, circadian rhythm and ligand-induced repression of the human glucocorticoid receptor. BMC Endocr. Disord. 14, 71 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
- 10.J. Lee, S. Lee, S. Chung, N. Park, G.H. Son, H. An, J. Jang, D.J. Chang, Y.G. Suh, K. Kim, Identification of a novel circadian clock modulator controlling BMAL1 expression through a ROR/REV-ERB-response element-dependent mechanism. Biochem. Biophys. Res. Commun. 469, 580–586 (2016)CrossRefPubMedGoogle Scholar
- 13.M.G. Pavlatou, K.C. Vickers, S. Varma, R. Malek, M. Sampson, A.T. Remaley, P.W. Gold, M.C. Skarulis, T. Kino, Circulating cortisol-associated signature of glucocorticoid-related gene expression in subcutaneous fat of obese subjects. Obesity 21, 960–967 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
- 14.N. Nader, G.P. Chrousos, T. Kino, Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J. 23, 1572–1583 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
- 15.S. Karaki, G. Garcia, C. Tcherakian, F. Capel, T. Tran, M. Pallardy, M. Humbert, D. Emilie, V. Godot, Enhanced glucocorticoid-induced leucine zipper in dendritic cells induces allergen-specific regulatory CD4( + ) T-cells in respiratory allergies. Allergy 69, 624–631 (2014)CrossRefPubMedGoogle Scholar
- 17.B. Ergun-Longmire, N.K. Maclaren, Autoimmune Polyglandular Syndromes. L.J. De Groot, G. Chrousos, K. Dungan, K.R. Feingold, A. Grossman, J.M. Hershman, C. Koch, M. Korbonits, R. McLachlan, M. New, J. Purnell, R. Rebar, F. Singer, A. Vinik (eds.) Endotext [Internet]. MDText.com, Inc.: South Dartmouth (MA) (2014)Google Scholar
- 19.K. Aung, Type III polyglandular autoimmune syndrome. Medscape (2014). http://emedicine.medscape.com/article/124398-overview
- 20.S.R. Bornstein, B. Allolio, W. Arlt, A. Barthel, Don-A. Wauchope, G.D. Hammer, E.S. Husebye, D.P. Merke, M.H. Murad, C.A. Stratakis, D.J. Torpy, Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 101, 364–389 (2016)CrossRefPubMedGoogle Scholar
- 21.E.S. Husebye, B. Allolio, W. Arlt, K. Badenhoop, S. Bensing, C. Betterle, A. Falorni, E.H. Gan, A.L. Hulting, A. Kasperlik-Zaluska, O. Kämpe, K. Løvås, G. Meyer, S.H. Pearce;, Consensus statement on the diagnosis, treatment and follow-up of patients withprimary adrenal insufficiency. J. Intern. Med. 275, 104–115 (2014)CrossRefPubMedGoogle Scholar
- 32.C.M. Spies, P. Hoff, J. Mazuch, T. Gaber, B. Maier, C. Strehl, M. Hahne, M. Jakstadt, D. Huscher, G.R. Burmester, J. Detert, A. Kramer, F. Buttgereit, Circadian rhythms of cellular immunity in rheumatoid arthritis: a hypothesis-generating study. Clin. Exp. Rheumatol. 33, 34–43 (2015)PubMedGoogle Scholar
- 33.O. Palmieri, G. Mazzoccoli, F. Bossa, R. Maglietta, O. Palumbo, N. Ancona, G. Corritore, T. Latiano, G. Martino, R. Rubino, G. Biscaglia, D. Scimeca, M. Carella, V. Annese, A. Andriulli, A. Latiano, Systematic analysis of circadian genes using genome-wide cDNA microarrays in the inflammatory bowel disease transcriptome. Chronobiol. Int. 32(7), 903–916 (2015)CrossRefPubMedGoogle Scholar
- 38.M.L. Spengler, K.K. Kuropatwinski, M. Comas, A.V. Gasparian, N. Fedtsova, A.S. Gleiberman II, N.M. Gitlin, K.A. Artemicheva, A.V. Deluca, M.P. Gudkov, Antoch; Core circadian protein CLOCK is a positive regulator of NF-κB-mediated transcription. Proc. Natl. Acad. Sci. U.S.A. 109, 2457–2465 (2012)CrossRefGoogle Scholar
- 42.E.V. Dang, J. Barbi, H.Y. Yang, D. Jinasena, H. Yu, Y. Zheng, Z. Bordman, J. Fu, Y. Kim, H.R. Yen, W. Luo, K. Zeller, L. Shimoda, S.L. Topalian, G.L. Semenza, C.V. Dang, D.M. Pardoll, F. Pan, Control of T(H)17/;T(reg) balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011)CrossRefPubMedPubMedCentralGoogle Scholar