Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Effects of Early Life Stress on the Development of Depression and Epigenetic Mechanisms of p11 Gene

생애 초기 유해 경험이 우울증의 발병과 p11 유전자의 후성유전기전에 미치는 영향

  • Seo, Mi Kyoung (Paik Institute for Clinical Research, Inje University) ;
  • Choi, Ah Jeong (Paik Institute for Clinical Research, Inje University) ;
  • Lee, Jung Goo (Paik Institute for Clinical Research, Inje University) ;
  • Urm, Sang-Hwa (Department of Preventive Medicine, College of Medicine, Inje University) ;
  • Park, Sung Woo (Paik Institute for Clinical Research, Inje University) ;
  • Seog, Dae-Hyun (Department of Biochemistry, College of Medicine, Inje University)
  • 서미경 (인제대학교 백인제기념임상의학연구소) ;
  • 최아정 (인제대학교 백인제기념임상의학연구소) ;
  • 이정구 (인제대학교 백인제기념임상의학연구소) ;
  • 엄상화 (인제대학교 의과대학 예방의학교실) ;
  • 박성우 (인제대학교 백인제기념임상의학연구소) ;
  • 석대현 (인제대학교 의과대학 생화학교실)
  • Received : 2019.04.02
  • Accepted : 2019.04.22
  • Published : 2019.09.30
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Abstract

Early life stress (ELS) increases the risk of depression. ELS may be involved in the susceptibility to subsequent stress exposure during adulthood. We investigated whether epigenetic mechanisms of p11 promoter affect the vulnerability to chronic unpredictable stress (CUS) induced by the maternal separation (MS). Mice pups were separated from their dams (3 hr/day from P1-P21). When the pups reached adulthood, we applied CUS (daily for 3 weeks). The levels of hippocampal p11 expression were analyzed by quantitative real-time PCR. The levels of acetylated and methylated histone H3 at p11 promoter were measured by chromatin immunoprecipitation. Depression-like behavior was measured by the forced swimming test (FST). The MS and CUS group exhibited significant decreases in p11 mRNA level and the MS plus CUS group had a greater reduction in this level than the CUS group. The MS plus CUS group also resulted in greater reduction in H3 acetylation than the CUS group. This reduction was associated with an upregulation of histone deacetylase 5. Additionally, the MS plus CUS group showed a greater decrease in H3K4met3 level and a greater increase in H3K27 met3 level than the CUS group. Consistent with the reduction of p11 expression, the MS plus CUS group displayed longer immobility times in the FST compared to the control group. Mice exposed to MS followed by CUS had much greater epigenetic alterations in the hippocampus compared to adult mice that only experienced CUS. ELS can exacerbate the effect of stress exposure during adulthood through histone modification of p11 gene.

생애 초기 유해 경험은 우울증의 위험성을 높이며, 성인기 스트레스의 민감성에 영향을 미칠 수 있다. 출생 후 모성 분리(MS)로 인한 성인기 스트레스(장기간 예측 불가능한 스트레스; CUS)의 취약성에 p11 유전자의 후성유전기전이 영향을 미치는 지를 확인하였다. 출생 직후부터 21일 동안 하루 3시간 동안 새끼 생쥐를 어미 생쥐로부터 분리시켜 새끼 생쥐가 성체가 되었을 때 CUS를 3주 동안 매일 적용하였다. Real time PCR기법으로 해마의 p11 발현 양을 측정하였고, 염색질 면역 침전 분석법으로 p11 promoter의 히스톤 H3 아세틸화 및 메틸화 양을 측정하였다. 강제수영검사에서 우울 유사 행동을 측정하였다. MS군 및 CUS군은 p11 mRNA 발현 양을 유의하게 감소시켰으며, MS+CUS군은 CUS군에 비해 p11 발현 양을 유의하게 증가시켰다. 또한 MS+CUS군은 CUS군에 비해 H3 아세틸화를 감소시켰다. 이러한 감소는 HDAC5 mRNA 발현 증가와 일치하였다. MS+CUS군은 CUS군에 비해 H3K4 메틸화를 감소시켰으며, H3K27 메틸화를 증가시켰다. 강제수영검사에서 p11 발현이 가장 많이 감소된 MS+CUS군이 대조군에 비해 더 긴 부동 시간을 나타내었다. 출생 후 모성 분리를 경험하고 성체 기간에 스트레스를 함께 받은 생쥐는 성체기간에만 스트레스를 받은 생쥐보다 훨씬 더 큰 후성유전 변화를 보여주었다. 생애 초기 유해 경험은 해마에서 p11 유전자의 히스톤 변형을 통해 성체 스트레스 효과를 더 악화시키는 것으로 생각된다.

Keywords

References

  1. Banasr, M., Valentine, G. W., Li, X. Y., Gourley, S. L., Taylor, J. R. and Duman, R. S. 2007. Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol. Psychiatry 62, 496-504. https://doi.org/10.1016/j.biopsych.2007.02.006
  2. Borrelli, E., Nestler, E. J., Allis, C. D. and Sassone-Corsi, P. 2008. Decoding the epigenetic language of neuronal plasticity. Neuron 60, 961-974. https://doi.org/10.1016/j.neuron.2008.10.012
  3. Boulle, F., van den Hove, D. L., Jakob, S. B., Rutten, B. P., Hamon, M., van Os, J., Lesch, K. P., Lanfumey, L., Steinbusch, H. W. and Kenis, G. 2012. Epigenetic regulation of the BDNF gene: implications for psychiatric disorders. Mol. Psychiatry 17, 584-596. https://doi.org/10.1038/mp.2011.107
  4. Choi, J. K. and Howe, L. J. 2009. Histone acetylation: truth of consequences? Biochem. Cell Biol. 87, 139-150. https://doi.org/10.1139/O08-112
  5. de Ruijter, A. J., van Gennip, A. H., Caron, H. N., Kemp, S. and van Kuilenburg, A. B. 2003. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem. J. 370, 737-749. https://doi.org/10.1042/bj20021321
  6. Egeland, M., Warner-Schmidt, J., Greengard, P. and Svenningsson, P. 2010. Neurogenic effects of fluoxetine are attenuated in p11 (S100A10) knockout mice. Biol. Psychiatry 67, 1048-1056. https://doi.org/10.1016/j.biopsych.2010.01.024
  7. Erburu, M., Munoz-Cobo, I., Dominguez-Andres, J., Beltran, E., Suzuki, T., Mai, A., Valente, S., Puerta, E. and Tordera, R. M. 2015. Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. Eur. Neuropsychopharmacol. 25, 2036-2048. https://doi.org/10.1016/j.euroneuro.2015.08.016
  8. Farrell, C. and O'Keane, V. 2016. Epigenetics and the glucocorticoid receptor: a review of the implications in depression. Psychiatry Res. 242, 349-356. https://doi.org/10.1016/j.psychres.2016.06.022
  9. Heim, C. and Nemeroff, C. B. 2001. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol. Psychiatry 49, 1023-1039. https://doi.org/10.1016/S0006-3223(01)01157-X
  10. Hobara, T., Uchida, S., Otsuki, K., Matsubara, T., Funato H., Matsuo, K., Suetsugi, M. and Watanabe, Y. 2010. Altered gene expression of histone deacetylases in mood disorder patients. J. Psychiatr. Res. 44, 263-270. https://doi.org/10.1016/j.jpsychires.2009.08.015
  11. Izzo, A. and Schneider, R. 2010. Chatting histone modifications in mammals. Brief Funct. Genomics 9, 429-443. https://doi.org/10.1093/bfgp/elq024
  12. Kendler, K. S., Sheth, K., Gardner, C. O. and Prescott, C. A. 2002. Childhood parental loss and risk for first-onset of major depression and alcohol dependence: the time-decay of risk and sex differences. Psychol. Med. 32, 1187-1194. https://doi.org/10.1017/S0033291702006219
  13. Li, H. Y., Jiang, Q. S., Fu, X. Y., Jiang, X. H., Zhou, Q. X. and Qiu, H. M. 2017. Abnormal modification of histone acetylation involved in depression-like behaviors of rats induced by chronically unpredicted stress. Neuroreport 28, 1054-1060. https://doi.org/10.1097/WNR.0000000000000879
  14. McGowan, P. O., Suderman, M., Sasaki, A., Huang, T. C., Hallett, M., Meaney, M. J. and Szyf, M. 2011. Broad epigenetic signature of maternal care in the brain of adult rats. PLoS One 6, e14739. https://doi.org/10.1371/journal.pone.0014739
  15. Melas, P. A., Rogdaki, M., Lennartsson, A., Bjork, K., Qi, H., Witasp, A., Werme, M., Wegener, G., Mathe, A. A., Svenningsson, P. and Lavebratt, C. 2012. Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression. Int. J. Neuropsychopharmacol. 15, 669-679. https://doi.org/10.1017/S1461145711000940
  16. Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmuhl, Y., Fischer, D., Holsboer, F., Wotjak, C. T., Almeida, O. F. and Spengler, D. 2009. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurocsi. 12, 1559-1566. https://doi.org/10.1038/nn.2436
  17. Neyazi, A., Theilmann, W., Brandt, C., Rantamaki, T., Matsui, N., Rhein, M., Kornhuber, J., Bajbouj, M., Sperling, W., Bleich, S., Frieling, H. and Loscher, W. 2018. p11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy. Transl. Psychiatry 8, 25. https://doi.org/10.1038/s41398-017-0077-3
  18. Porsolt, R. D., Le Pichon, M. and Jalfre, M. 1977. Depression: a new animal model sensitive to antidepressant treatments. Nature 266, 730-732. https://doi.org/10.1038/266730a0
  19. Seo, M. K., Ly, N. N., Lee, C. H., Cho, H. Y., Choi, C. M., Nhu, L. H., Lee, J. G., Lee, B. J., Kim, G. M., Yoon, B. J., Park, S. W. and Kim, Y. H. 2016. Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus. Neuropharmacology 105, 388-397. https://doi.org/10.1016/j.neuropharm.2016.02.009
  20. St-Cyr, S. and McGowan, P. O. 2015. Programming of stressrelated behavior and epigenetic neural gene regulation in mice offspring through maternal exposure to predator odor. Front Behav. Neurosci. 9, 145. https://doi.org/10.3389/fnbeh.2015.00145
  21. Sun, H., Kennedy, P. J. and Nestler, E. J. 2013. Epigenetics of the depressed brain: role of histone acetylation and methylation. Neuropsychopharmacology 38, 124-137. https://doi.org/10.1038/npp.2012.73
  22. Svenningsson, P., Chergui, K., Rachleff, I., Flajolet, M., Zhang, X., El Yacoubi, M., Vaugeois, J. M., Nomikos, G. G. and Greengard, P. 2006. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311, 77-80. https://doi.org/10.1126/science.1117571
  23. Svenningsson, P., Kim, Y., Warner-Schmidt, J., Oh, Y. S. and Greengard, P. 2013. p11 and its role in depression and therapeutic responses to antidepressants. Nat. Rev. Neurosci. 14, 673-680. https://doi.org/10.1038/nrn3564
  24. Theilmann, W., Kleimann, A., Rhein, M., Bleich, S., Frieling, H., Loscher, W. and Brandt, C. 2016. Behavioral differences of male Wistar rats from different vendors in vulnerability and resilience to chronic mild stress are reflected in epigenetic regulation and expression of p11. Brain Res. 1642, 505-515. https://doi.org/10.1016/j.brainres.2016.04.041
  25. Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L. and Nestler, E. J. 2006. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat. Neurosci. 9, 519-525. https://doi.org/10.1038/nn1659
  26. Turecki, G. and Meaney, M. J. 2016. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol. Psychiatry 79, 87-96. https://doi.org/10.1016/j.biopsych.2014.11.022
  27. Vogelauer, M., Wu, J., Suka, N. and Grunstein, M. 2000. Global histone acetylation and deacetylation in yeast. Nature 408, 495-498. https://doi.org/10.1038/35044127
  28. Warner-Schmidt, J. L., Chen, E. Y., Zhang, X., Marshall, J. J., Morozov, A., Svenningsson, P. and Greengard, P. 2010. A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol. Psychiatry 68, 528-535. https://doi.org/10.1016/j.biopsych.2010.04.029
  29. Warner-Schmidt, J. L., Flajolet, M., Maller, A., Chen, E. Y., Qi, H., Svenningsson, P. and Greengard, P. 2009. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. J. Neurosci. 29, 1937-1946. https://doi.org/10.1523/JNEUROSCI.5343-08.2009
  30. Weaver, I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M. and Meaney, M. J. 2004. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847-854. https://doi.org/10.1038/nn1276
  31. Weaver, I. C., D'Alessio, A. C., Brown, S. E., Hellstrom, I. C., Dymov, S., Sharma, S., Szyf, M. and Meaney, M. J. 2007. The transcription factor nerve growth factor-inducible protein a mediates epigenetic programming: altering epigenetic marks by immediate-early genes. J. Neurosci. 27, 1756-1768. https://doi.org/10.1523/JNEUROSCI.4164-06.2007
  32. Willner, P. 2005. Chronic mild stress (CMS) revisited: consistency and behavioural- neurobiological concordance in the effects of CMS. Neuropsychobiology 52, 90-110. https://doi.org/10.1159/000087097
  33. Wu, R., Shui, L., Wang, S., Song, Z. and Tai, F. 2016. Bilobalide alleviates depression-like behavior and cognitive deficit induced by chronic unpredictable mild stress in mice. Behav. Pharmacol. 27, 596-605. https://doi.org/10.1097/FBP.0000000000000252