Effects of Psychosocial Stress on the Gene Expression of the Clock Genes hPER1 and hPER2 in Humans

Elvira A. Abbruzzese, Thomas Birchler, Ulrike Ehlert

Department of Clinical Psychology and Psychotherapy, Psychological Institute, University of Zurich, Zurich, Switzerland.
Division of Neuroimmunology, Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Zurich, Switzerland.

DOI: 10.4236/psych.2014.51012                

Abstract

The circadian clock is a self-sustained time-keeping system which controls behavioral, biochemical and physiological rhythmic processes. In mammals, the cogwheels of this clock are the so-called clock genes which control their own expression via several feedback loops. One of these genes is hPER1, a clock gene which disposes of a glucocorticoid-responsive element and might therefore be influenced by glucocorticoids. In humans, stress is associated with an increase in the glucocorticoid cortisol and is seen as a major factor in the etiology of numerous mental health problems. For this reason, our goal was to investigate the putative cortisol-mediated influence of acute and chronic psychosocial stress on the gene expression of hPER1 as well as hPER2, another related clock gene from the same family. We therefore applied laboratory psychosocial stress to thirty-one healthy men and measured cortisol as well as mRNA levels of hPER1 and hPER2. Our main findings suggest that acute psychosocial stress influences the expression of hPER1 and hPER2 dependent on the subjective experience of chronic stress. We therefore conclude that the reactivity to acute stress on the gene expression level of these two genes differs significantly between subjects with high chronic stress compared to subjects with low chronic stress.

Keywords

Circadian Rhythm; Clock Genes; Cortisol; Gene Expression; hPER1; hPER2; Psychosocial Stress; Biological Clock

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Albrecht, U., & Eichele, G. (2003). The mammalian circadian clock. Current Opinion in Genetics & Development, 13, 271-277. http://dx.doi.org/10.1016/S0959-437X(03)00055-8 [Google Scholar] [CrossRef]
[2]	Albrecht, U. (2004). Human molecular chronotyping in sight? Genome Biology, 5, article 246.
[3]	Antya, N., Mandelli, L., Nearchou, F. A., Vaiopoulos, C., Stefanis, C. N., Serretti, A., & Stefanis, N. C. (2012). The 3111/C Polymorphism Interacts With Stressful Life Events to Influence Patterns of Sleep in Females. Chronobiology International, 29, 891-897. http://dx.doi.org/10.3109/07420528.2012.699380 [Google Scholar] [CrossRef] [PubMed]
[4]	Balsalobre, A., Brown, S. A., Marcacci, L., Tronche, F., Kellendonk, C., Reichardt, H. M., Schütz, G., & Schibler, U. (2000). Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science, 289, 2344-2347. http://dx.doi.org/10.1126/science.289.5488.2344 [Google Scholar] [CrossRef] [PubMed]
[5]	Benedetti, F., Dallaspezia, S., Colombo, C., Pirovano, A., Marino, E., & Smeraldi, E. (2008). A length polymorphism in the circadian clock gene Per3 influences age at onset of bipolar disorder. Neuroscience Letters, 445, 184-187. http://dx.doi.org/10.1016/j.neulet.2008.09.002 [Google Scholar] [CrossRef] [PubMed]
[6]	Bjarnason, G. A., Jordan, R. C. K., Wood, P. A., Li, Q., Lincoln, D. W., Sothern, R. B., Hrushesky, W. J. M., & Ben-David, Y. (2001). Circadian expression of clock genes in human oral mucosa and skin. American Journal of Clinical Pathology, 158, 1793-1801.
[7]	Brown, S. A., Fleury-Olela, F., Nagoshi, E., Hauser, C., Juge, C., Meier, C. A., Chicheportiche, R., Dayer, J. M., Albrecht, U., & Schibler, U. (2005). The period length of fibroblast circadian gene expression varies widely among human individuals. PLOS Biol., 3, 1813-1818. http://dx.doi.org/10.1371/journal.pbio.0030338 [Google Scholar] [CrossRef] [PubMed]
[8]	Buijs, R. M., van Eden, C. G., Concharuk, V. D., & Kalsbeek, A. (2003). The biological clock tunes the organs of the body: Timing by hormones and the autonomic nervous system. Journal of Endocrinology, 177, 17-26. http://dx.doi.org/10.1677/joe.0.1770017 [Google Scholar] [CrossRef] [PubMed]
[9]	Cajochen, C., Jud, C., Münch, M., Kobialka, S., Wirz-Justice, A., & Albrecht, U. (2006). Evening exposure to blue light stimulates the expression of the clock gene PER2 in humans. European Journal of Neuroscience, 23, 1082-1086. http://dx.doi.org/10.1111/j.1460-9568.2006.04613.x [Google Scholar] [CrossRef] [PubMed]
[10]	Cavadini, G., Petrzilka, S., Kohler, P., Jud, C., Tobler, I., Birchler, T., & Fontana, A. (2007). TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proceedings of the National Academy of Sciences, 104, 12843-12848. http://dx.doi.org/10.1073/pnas.0701466104 [Google Scholar] [CrossRef] [PubMed]
[11]	Costa e Silva, J. A. (2006). Sleep disorders in psychiatry. Metabolism, 55, 40-44. http://dx.doi.org/10.1016/j.metabol.2006.07.012 [Google Scholar] [CrossRef] [PubMed]
[12]	Czeisler, C. A., Duffy, J. F., Shanahan, T. L., Brown, E. N., Mitchell, J. F., Rimmer, D. W., Ronda, J. M., Silva, E. W., Allan, J. S., Emens, J. S., Dijk, D. J., & Kronauer, R. E. (1999). Stability, precision, and near-24-hour period of the human circadian pacemaker. Science, 284, 2177-2181. http://dx.doi.org/10.1126/science.284.5423.2177 [Google Scholar] [CrossRef] [PubMed]
[13]	Dallmann, R., Touma, C., Palme, R., Albrecht, U., & Steinlechner, S. (2006). Impaired daily glucocorticoid rhythm in Per1Brd mice. Journal of Comparative Physiology A, 192, 769-775. http://dx.doi.org/10.1007/s00359-006-0114-9 [Google Scholar] [CrossRef] [PubMed]
[14]	Damiola, F., Le Minh, N., Preitner, N., Kornmann, B., Fleury-Olela, F., & Schibler, U. (2000). Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes & Development, 14, 2950-2961. http://dx.doi.org/10.1101/gad.183500 [Google Scholar] [CrossRef] [PubMed]
[15]	Dickmeis, T., Lahiri, K., Nica, G., Vallone, D., Santoriello, C., Neumann, C. J., Hammerschmidt, M., & Foulkes, N. S. (2007). Glucocorticoid Play a Key Role in Circadian Cell Cycle Rhythms. PLOS Biol., 5, 854-864. http://dx.doi.org/10.1371/journal.pbio.0050078 [Google Scholar] [CrossRef] [PubMed]
[16]	Ehlert, U., Nater, U. M., & Bohmelt, A. (2005). High and low unstimulated salivary cortisol levels correspond to different symptoms of functional gastrointestinal disorders. Journal of Psychosomatic Research, 59, 7-10. http://dx.doi.org/10.1016/j.jpsychores.2005.03.005 [Google Scholar] [CrossRef] [PubMed]
[17]	Fu, L., Pelicano, H., Liu, J., Huang, P., & Lee, C. C. (2002). The circadian gene Period2 plays an important role in tumor suppression and DNA damage responses in vivo. Cell, 111, 41-50. http://dx.doi.org/10.1016/S0092-8674(02)00961-3 [Google Scholar] [CrossRef]
[18]	Fukuoka, Y., Burioka, N., Takata, M., Ohdo, S., Miyata, M., Endo, M., & Shimizu, E. (2005). Glucocorticoid administration increases hPER1 mRNA Levels in human peripheral blood mononuclear cells in vitro or in vivo. Journal of Biological Rhythms, 20, 550-553. http://dx.doi.org/10.1177/0748730405279866 [Google Scholar] [CrossRef] [PubMed]
[19]	Gaab, J., Rohleder, N., Heitz, V., Engert, V., Schad, T., Schürmeyer, T. H., & Ehlert, U. (2005). Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome. Psychoneuroendocrinology, 30, 188-198. http://dx.doi.org/10.1016/j.psyneuen.2004.06.008 [Google Scholar] [CrossRef] [PubMed]
[20]	Godbout, J. F., & Glaser, R. (2006). Stress-induced immune dysregulation: Implications for wound healing, infectious disease and cancer. Journal of NeuroImmune Pharmacology, 1, 421-427. http://dx.doi.org/10.1007/s11481-006-9036-0 [Google Scholar] [CrossRef] [PubMed]
[21]	Haimovich, B., Calvano, J., Haimovich, A. D., Calvano, S. E., Coyle, S. M., & Lowry, S. F. (2010). In vivo endotoxin synchronizes and suppresses clock gene expression in human peripheral blood leukocytes. Critical Care Medicine, 38, 751-758. http://dx.doi.org/10.1097/CCM.0b013e3181cd131c [Google Scholar] [CrossRef]
[22]	Heinrichs, M., Wagner, D., Schoch, W., Soravia, L. M., Hellhammer, D. H., & Ehlert, U. (2005). Predicting posttraumatic stress symptoms from pretraumatic risk factors: A 2-year prospective follow-up study in firefighters. American Journal of Psychiatry, 162, 2276-2286. http://dx.doi.org/10.1176/appi.ajp.162.12.2276 [Google Scholar] [CrossRef] [PubMed]
[23]	Ishida, A., Mutoh, T., Ueyama, T., Bando, H., Masubuchi, S., Nakahara, D., Tsujimoto, G., & Okamura, H. (2005). Light activates the adrenal gland: Timing of gene expression and glucocorticoid release. Cell Metabolism, 2, 297-307. http://dx.doi.org/10.1016/j.cmet.2005.09.009 [Google Scholar] [CrossRef] [PubMed]
[24]	Kasukawa, T., Sugimoto, M., Hida, A., Minami, Y., Mori, M., Honma, S., Honma, K., Mishima, K., Soga, T., & Uedo, H. R. (2012). Human blood metabolite timetable indicates internal body time. Proceedings of the National Academy of Sciences, 109, 15036-15041. http://dx.doi.org/10.1073/pnas.1207768109 [Google Scholar] [CrossRef] [PubMed]
[25]	Kirschbaum, C., Pirke, K. M., & Hellhammer, D. H. (1993). The “Trier Social Stress Test”—A tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology, 28, 76-81. http://dx.doi.org/10.1159/000119004 [Google Scholar] [CrossRef] [PubMed]
[26]	Kirschbaum, C., & Hellhammer, D. H. (2007). Encyclopedia of stress (pp. 405-409). Oxford: Academic Press, http://dx.doi.org/10.1016/B978-012373947-6.00334-2 [Google Scholar] [CrossRef]
[27]	Kudielka, B. M., Schommer, N. C., Hellhammer, D. H., & Kirschbaum, C. (2003). Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day. Psychoneuroendocrinology, 29, 983-992. http://dx.doi.org/10.1016/j.psyneuen.2003.08.009 [Google Scholar] [CrossRef] [PubMed]
[28]	Ko, C. H., & Takahashi, J. S. (2006). Molecular components of the mammalian circadian clock. Human Molecular Genetics, 15, R271-R277. http://dx.doi.org/10.1093/hmg/ddl207 [Google Scholar] [CrossRef] [PubMed]
[29]	Kriegsfeld, R. J., & Silver, R. (2006). The regulation of neuroendocrine function: Timing is everything. Hormones and Behavior, 49, 557-574. http://dx.doi.org/10.1016/j.yhbeh.2005.12.011 [Google Scholar] [CrossRef] [PubMed]
[30]	Kudielka, B. M., Hellhammer, D. H., & Wüst, S. (2009). Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology, 34, 2-18. http://dx.doi.org/10.1016/j.psyneuen.2008.10.004 [Google Scholar] [CrossRef] [PubMed]
[31]	Lévi, F., Filipski, E., Iuriski, I., Li, X. M., & Innominato, P. (2007). Cross-talks between circadian timing system and cell division cycle determine cancer biology and therapeutics. Cold Spring Harbor Symposia on Quantitative Biology, 72, 465-475. http://dx.doi.org/10.1101/sqb.2007.72.030 [Google Scholar] [CrossRef] [PubMed]
[32]	Lévi, F., & Schibler, U. (2007). Circadian Rhythms: Mechanisms and Therapeutic Implications. Annual Review of Pharmacology and Toxicology, 47, 593-628. http://dx.doi.org/10.1146/annurev.pharmtox.47.120505.105208 [Google Scholar] [CrossRef] [PubMed]
[33]	Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J., & Foster, R. G. (1999). Non-rod, non-cone ocular photoreceptors regulate the mammalian pineal. Science, 284, 505-507. http://dx.doi.org/10.1126/science.284.5413.505 [Google Scholar] [CrossRef] [PubMed]
[34]	McEwan, B., & Lasley, E. N. (2003). Allostatic load: When protection gives way to damage. Advances in Mind-Body Medicine, 19, 28-33.
[35]	Nader, N., Chrousos, G. P., & Kino, T. (2009). Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: Potential physiological implications. FASEB Journal, 23, 1572-1583. http://dx.doi.org/10.1096/fj.08-117697 [Google Scholar] [CrossRef] [PubMed]
[36]	Okada, K., Yano, M., Doki, Y., Azama, T., Iwanaga, H., Miki, H., Nakayama, M., Miyata, H., Takiguchi, S., Fujiwara, Y., Yasuda, T., Ishida, N., & Monden, M. (2006). Injection of LPS causes transient suppression of biological clock genes in rats. Journal of Surgical Research, 145, 5-12. http://dx.doi.org/10.1016/j.jss.2007.01.010 [Google Scholar] [CrossRef] [PubMed]
[37]	Pagani, L., Semenova, E. A., Moriggi, E., Revell, V. L., Hack, L. M., Lockley, S. W., Arendt, J., Skene, D. J., Meier, F., Izakovic, J., WirzJustice, A., Cajochen, C., Sergeeva, O. J., Cheresiz, S. V., Danilenko, K. V., Eckert, A., & Brown, S. A. (2010). The physiological period length of the human circadian clock in vivo is directly proportional to period in human fibroblasts. PLoS ONE, 5, e13376. http://dx.doi.org/10.1371/journal.pone.0013376 [Google Scholar] [CrossRef] [PubMed]
[38]	Panda, S., Hogensch, J. B., & Kay, S. A. (2002). Circadian rhythms from flies to human. Nature, 417, 329-335. http://dx.doi.org/10.1038/417329a [Google Scholar] [CrossRef] [PubMed]
[39]	Peng, Z., Chen, X., & Wei, Z. (2007). Cryptochrome 1 maybe a candidate gene of schizophrenia. Medical Hypotheses, 69, 849-851. http://dx.doi.org/10.1016/j.mehy.2007.02.003 [Google Scholar] [CrossRef] [PubMed]
[40]	Peugh, J. L., & Enders, C. K. (2005). Using the SPSS mixed procedure to fit cross-sectional and longitudinal multilevel models. Educational and Psychological Measurement, 65, 717-741. http://dx.doi.org/10.1177/0013164405278558 [Google Scholar] [CrossRef]
[41]	Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoneuroendocrinology, 28, 916-931. http://dx.doi.org/10.1016/S0306-4530(02)00108-7 [Google Scholar] [CrossRef]
[42]	Ralph, M. R., Foster, R. G., Davis, F. C., & Menaker, M. (1990). Transplanted suprachiasmatic nucleus determines circadian period. Science, 247, 975-978. http://dx.doi.org/10.1126/science.2305266 [Google Scholar] [CrossRef] [PubMed]
[43]	Reppert, S. M., & Weaver, D. R. (2002). Coordination of circadian timing in mammals. Nature, 418, 935-941. http://dx.doi.org/10.1038/nature00965 [Google Scholar] [CrossRef] [PubMed]
[44]	Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., Vitaterna, M. H., Orsulak, P., Takahashi, J. S., Nestler, E. J., Carlezon Jr., W. A., & McClung, C. (2007). Mania-like behavior induced by disruption of CLOCK. Proceedings of the National Academy of Sciences of the United States of America, 104, 6406-6411. http://dx.doi.org/10.1073/pnas.0609625104 [Google Scholar] [CrossRef] [PubMed]
[45]	Scheer, F. A., & Buijs, R. M. (1999). Light affects morning salivary cortisol in humans. The Journal of Clinical Endocrinology and Metabolism, 84, 3395-3398. http://dx.doi.org/10.1210/jc.84.9.3395 [Google Scholar] [CrossRef] [PubMed]
[46]	Schibler, U., Rippberger, J., & Brown, S. A. (2003). Peripheral circadian oscillators in mammals: Time and food. Journal of Biological Rhythms, 18, 250-260. http://dx.doi.org/10.1177/0748730403018003007 [Google Scholar] [CrossRef] [PubMed]
[47]	Schulz, P., & Schlotz, W. (1999). Das trierer inventar zur erfassung von chronischem streß (TICS): Skalenkonstruktion, teststatistische überprüfung und validierung der Skala Arbeitsüberlastung. Diagnostica, 45, 8-19. http://dx.doi.org/10.1026//0012-1924.45.1.8 [Google Scholar] [CrossRef]
[48]	So, A. Y. L., Bernal, T. U., Pillsbury, M. L., Yamamoto, K. R., & Feldman, B. J. (2009). Glucocorticoid regulation of the circadian clock modulates glucose homeostasis. Proceedings of the National Academy of Sciences of the United States of America, 106, 17582-17587. http://dx.doi.org/10.1073/pnas.0909733106 [Google Scholar] [CrossRef] [PubMed]
[49]	Stevens, R. G. (2005). Circadian disruption and breast cancer, from melatonin to clock genes. Epidemiology, 16, 254-258. http://dx.doi.org/10.1097/01.ede.0000152525.21924.54 [Google Scholar] [CrossRef] [PubMed]
[50]	Stokkan, K. A., Yamazaki, S., Tei, H., Sakaki, Y., & Menaker, M. (2001). Entrainment of the circadian clock in the liver by feeding. Science, 291, 490-493. http://dx.doi.org/10.1126/science.291.5503.490 [Google Scholar] [CrossRef] [PubMed]
[51]	Takahashi, S., Yokota, S., Hara, R., Kobayashi, T., Akiyama, M., Moriya, T., & Shibata, S. (2001). Physical and inflammatory stressors elevate circadian clock gene mPer1 mRNA levels in the paraventricular nucleus of the mouse. Endocrinology, 142, 4910-4917. http://dx.doi.org/10.1210/en.142.11.4910 [Google Scholar] [CrossRef] [PubMed]
[52]	Teboul, M., Barrat-Petit, M. A., Li, X. M., Claustrat, B., Formento, J. L., Delaunay, F., Levi, F., & Milano, G. (2005). Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells. Journal of Molecular Medicine, 83, 693-699. http://dx.doi.org/10.1007/s00109-005-0697-6 [Google Scholar] [CrossRef] [PubMed]
[53]	Viola, A. U., Archer, S. N., James, L. M., Groeger, J. A., Lo, J. C. Y., Skene, D. J., von Schantz, M., & Dijk, D. J. (2007). PER3 polymorphism predicts sleep structure and waking performance. Current Biology, 17, 613-618. http://dx.doi.org/10.1016/j.cub.2007.01.073 [Google Scholar] [CrossRef] [PubMed]
[54]	Wang, X., Mozhui, K., Li, Z., Mulligan, M. K., Ingels, J. F., Zhou, X., Hori, R. T., Chen, H., Cook, M. N., Williams, R. W., & Lu, L. (2012). A promoter polymorphism in the Per3 gene is associated with alcohol and stress response. Translational Psychiatry, 2, e73.
[55]	Wirtz, P. H., von Kanel, R., Emini, L., Suter, T., Fontana, A., & Ehlert, U. (2007). Variations in anticipatory cognitive stress appraisal and differential proinflammaotry cytokine expression in response to acute stress. Brain, Behavior, and Immunity, 21, 651-659. http://dx.doi.org/10.1016/j.bbi.2007.02.003 [Google Scholar] [CrossRef] [PubMed]
[56]	Woon, P. Y., Kaisaki, P. J., Braganca, J., Bihoreau, M. T., Levy, J. C., Farrall, M., & Gauguier, D. (2007). Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 104, 14412-14417. http://dx.doi.org/10.1073/pnas.0703247104 [Google Scholar] [CrossRef] [PubMed]
[57]	Yamamoto, T., Nakahata, Y., Tanaka, M., Yoshida, M., Soma, H., Shinohara, K., Yasuda, A., Mamine, T., & Takumi, T. (2005). Acute physical stress elevates mouse period1 mRNA expression in mouse peripheral tissues via a glucocorticoid-responsive element. Journal of Biological Chemistry, 280, 42036-42043. http://dx.doi.org/10.1074/jbc.M509600200 [Google Scholar] [CrossRef]
[58]	Yamazaki, S., Straume, M., Tei, H., Sakaki, Y., Menaker, M., & Block, G. D. (2002). Effects of aging on central and peripheral mammalian clocks. Proceedings of the National Academy of Sciences of the United States of America, 99, 10801-10806. http://dx.doi.org/10.1073/pnas.152318499 [Google Scholar] [CrossRef] [PubMed]