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Glucocorticoid Receptor Stimulation Resulting from Early Life Stress Affects Expression of DNA Methyltransferases in Rat Prefrontal Cortex

  • Mari Urb
  • Kaili Anier
  • Terje Matsalu
  • Anu Aonurm-Helm
  • Gunnar Tasa
  • Indrek Koppel
  • Alexander Zharkovsky
  • Tõnis Timmusk
  • Anti KaldaEmail author
Article
  • 93 Downloads

Abstract

Early life stress initiates long-term neurobiological changes that affect stress resilience and increased susceptibility to psychopathology. Maternal separation (MS) is used to cause early life stress and it induces profound neurochemical and behavioral changes that last until adulthood. The molecular pathways of how MS affects the regulation of DNA methyltransferases (Dnmt) in brain have not been entirely characterized. We evaluated MS effects on Dnmt1, Dnmt3a and Dnmt3b expression, DNMT enzyme activity and glucocorticoid receptor (GR) recruitment to different Dnmt loci in the prefrontal cortex (PFC) of Wistar rats. We found increased plasma corticosterone levels after MS that were associated with induced Dnmt expression and enzyme activity in rat PFC at post-natal day 15 (PND15). Chromatin immunoprecipitation showed increased binding of GR at the Dnmt3b promoter after MS, suggesting that genomic signaling of GR is an important regulatory mechanism for the induced Dnmt3b expression and DNMT activity. Although GR also binds to Dnmt3a promoter and a putative regulatory region in intron 3 in rat PFC, its expression after maternal separation may be influenced by other mechanisms. Therefore, GR could be a link between early life stress experience and long-term gene expression changes induced by aberrant DNA methylation.

Keywords

DNA methyltransferase Maternal separation Corticosterone Glucocorticoid receptor Prefrontal cortex Rat 

Notes

Acknowledgements

This study was supported by Estonian Research Council (grants PUT1686, institutional research funding IUT2-3 and IUT19-18) and European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012). The funding organizations we not involved in study design, data collection, analysis, interpretation of data, writing the paper and submitting the article for publication. The authors thank Miriam Ann Hickey for intellectual support and Ulla Peterson for technical assistance.

Author Contributions

AK, TT and AZ designed research. MU, KA, TM, GT, AA-H, IK acquired data and MU, KA, TM, AA-H, IK, AK performed data analysis. MU and AK wrote the paper. All authors critically reviewed content and approved the final version for publication.

Compliance with Ethical Standards

Conflict of Interest Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Anier K, Malinovskaja K, Pruus K, Aonurm-Helm A, Zharkovsky A, Kalda A (2014) Maternal separation is associated with DNA methylation and behavioural changes in adult rats. Eur Neuropsychopharmacol 24:459–468CrossRefGoogle Scholar
  2. Boku S, Toda H, Nakagawa S, Kato A, Inoue T, Koyama T et al (2015) Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biol Psychiatry 77:335–344CrossRefGoogle Scholar
  3. Cannella N, Oliveira AMM, Hemstedt T, Lissek T, Buechler E, Bading H et al (2018) Dnmt3a2 in the nucleus accumbens shell is required for reinstatement of cocaine seeking. J Neurosci 38(34):7516–7528CrossRefGoogle Scholar
  4. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A et al (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21(13):2933–2942CrossRefGoogle Scholar
  5. Chen T, Ueda Y, Xie S, Li E (2002) A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with Activede Novo methylation. J Biol Chem 277(41):38746–38754CrossRefGoogle Scholar
  6. Chocyk A, Bobula B, Dudys D, Przyborowska A, Majcher-Maslanka I, Hess G et al (2013) Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur J Neurosci 38:2089–2107CrossRefGoogle Scholar
  7. Cook SC, Wellman CL (2004) Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 60:236–248CrossRefGoogle Scholar
  8. Drouin J, Sun YL, Chamberland M, Gauthier Y, De Léan A, Nemer M et al (1993) Novel glucocorticoid receptor complex with DNA element of the hormone-repressed POMC gene. EMBO J 12(1):145–156CrossRefGoogle Scholar
  9. Elliott E, Manashirov S, Zwang R, Gil S, Tsoory M, Shemesh Y et al (2016a) Dnmt3a in the medial prefrontal cortex regulates anxiety-like behavior in adult mice. J Neurosci 36(3):730–740CrossRefGoogle Scholar
  10. Elliott EN, Sheaffer KL, Kaestner KH (2016b) The ‘de novo’ DNA methyltransferase Dnmt3b compensates the Dnmt1-deficient intestinal epithelium. Elife 5:e12975CrossRefGoogle Scholar
  11. Franklin TB, Russig H, Weiss IC, Gräff J, Linder N, Michalon A et al (2010) Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68:408–415CrossRefGoogle Scholar
  12. Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49:1023–1039CrossRefGoogle Scholar
  13. Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84CrossRefGoogle Scholar
  14. Ignácio ZM, Réus GZ, Abelaira HM, Maciel AL, de Moura AB, Matos D et al (2017) Quetiapine treatment reverses depressive-like behavior and reduces DNA methyltransferase activity induced by maternal deprivation. Behav Brain Res 320:225–232CrossRefGoogle Scholar
  15. Kalinyak JE, Griffin CA, Hamilton RW, Bradshaw JG, Perlman AJ, Hoffman AR (1989) Developmental and hormonal regulation of glucocorticoid receptor messenger RNA in the rat. J Clin Invest 84(6):1843–1848CrossRefGoogle Scholar
  16. Kessler RC, Davis CG, Kendler KS (1997) Childhood adversity and adult psychiatric disorder in the US National Comorbidity Survey. Psychol Med 27:1101–1119CrossRefGoogle Scholar
  17. Kuhn CM, Pauk J, Schanberg SM (1990) Endocrine responses to mother-infant separation in developing rats. Dev Psychobiol 23:395–410CrossRefGoogle Scholar
  18. Lee BH, Wen T-C, Rogido M, Sola A (2006) Glucocorticoid receptor expression in the cortex of the neonatal rat brain with and without focal cerebral ischemia. Neonatology 91(1):12–19CrossRefGoogle Scholar
  19. Levine S, Huchton DM, Wiener SG, Rosenfeld P (1991) Time course of the effect of maternal deprivation on the hypothalamic-pituitary-adrenal axis in the infant rat. Dev Psychobiol 24:547–558CrossRefGoogle Scholar
  20. Lister R, Pelizzola M, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J et al (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462:315–322CrossRefGoogle Scholar
  21. Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445CrossRefGoogle Scholar
  22. Lyko F (2018) The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet 19:81–92CrossRefGoogle Scholar
  23. Magariños AM, McEwen BS, Flügge G, Fuchs E (1996) Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 16:3534–3540CrossRefGoogle Scholar
  24. McCormick JA, Lyons V, Jacobson MD, Noble J, Diorio J, Nyirenda M et al (2000) 5′-heterogeneity of glucocorticoid receptor messenger RNA is tissue specific: differential regulation of variant transcripts by early-life events. Mol Endocrinol 14:506–517Google Scholar
  25. McCoy CR, Rana S, Stringfellow SA, Day JJ, Wyss JM, Clinton SM et al (2016) Neonatal maternal separation stress elicits lasting DNA methylation changes in the hippocampus of stress-reactive Wistar Kyoto rats. Eur J Neurosci 10:2829–2845CrossRefGoogle Scholar
  26. McEwen BS, Morrison JH (2013) Brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79:16–29CrossRefGoogle Scholar
  27. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348CrossRefGoogle Scholar
  28. Meadows JP, Guzman-Karlsson MC, Phillips S, Holleman C, Posey JL, Day JJ, Hablitz JJ, Sweatt JD (2015) DNA methylation regulates neuronal glutamatergic synaptic scaling. Sci Signal 8(382):ra61CrossRefGoogle Scholar
  29. Meadows JP, Guzman-Karlsson MC, Phillips S, Brown JA, Strange SK, Sweatt JD, Hablitz JJ (2016) Dynamic DNA methylation regulates neuronal intrinsic membrane excitability. Sci Signal 9(442):ra83CrossRefGoogle Scholar
  30. Meaney MJ, Aitken DH, van Berkel C, Bhatnagar S, Sapolsky RM (1988) Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 239:766–768CrossRefGoogle Scholar
  31. Meehan RR, Lewis JD, McKay S, Kleiner EL, Bird AP (1989) Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58:499–507CrossRefGoogle Scholar
  32. Moffett MC, Vicentic A, Kozel M, Plotsky P, Francis DD, Kuhar MJ (2007) Maternal separation alters drug intake patterns in adulthood in rats. Biochem Pharmacol 71:321–330CrossRefGoogle Scholar
  33. Monroy E, Hernandez-Torres E, Flores G (2010) Maternal separation disrupts dendritic morphology of neurons in prefrontal cortex, hippocampus, and nucleus accumbens in male rat offspring. J Chem Neuroanat 40:93–101CrossRefGoogle Scholar
  34. Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38:23–38CrossRefGoogle Scholar
  35. Nair A, Vadodaria KC, Banerjee SB, Benekareddy M, Dias BG, Duman RS et al (2007) Stressor-specific regulation of distinct brain-derived neurotrophic factor transcripts and cyclic AMP response element-binding protein expression in the postnatal and adult rat hippocampus. Neuropsychopharmacology 32:1504–1519CrossRefGoogle Scholar
  36. Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB et al (1985) Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab 61:536–540CrossRefGoogle Scholar
  37. Oakley RH, Cidlowski JA (2013) The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol 132:1033–1044CrossRefGoogle Scholar
  38. Oliveira AM, Hemstedt TJ, Bading H (2012) Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat Neurosci 15:1111–1113CrossRefGoogle Scholar
  39. Park SW, Seo MK, Lee JG, Hien LT, Kim YH (2018) Effects of maternal separation and antidepressant drug on epigenetic regulation of the brain-derived neurotrophic factor exon I promoter in the adult rat hippocampus. Psychiatry Clin Neurosci 72(4):255–265CrossRefGoogle Scholar
  40. Patel PD, Lopez JF, Lyons DM, Burke S, Wallace M, Schatzberg AF (2000) Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain. J Psychiatr Res 34:383–392CrossRefGoogle Scholar
  41. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
  42. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB, McEwen BS et al (2012) Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 153:4317–4327CrossRefGoogle Scholar
  43. Polman JA, de Kloet ER, Datson NA (2013) Two populations of glucocorticoid receptor-binding sites in the male rat hippocampal genome. Endocrinology 154(5):1832–1844CrossRefGoogle Scholar
  44. Pruunsild P, Sepp M, Orav E, Koppel I, Timmusk T (2011) Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene. J Neurosci 31(9):3295–3308CrossRefGoogle Scholar
  45. Pryce CR, Bettschen D, Feldon J (2001) Comparison of the effects of early handling and early deprivation on maternal care in the rat. Dev Psychobiol 38:239–251CrossRefGoogle Scholar
  46. Ratka A, Sutanto W, Bloemers M, de Kloet ER (1989) On the role of brain mineralocorticoid (type I) and glucocorticoid (type II) receptors in neuroendocrine regulation. Neuroendocrinology 50(2):117–123CrossRefGoogle Scholar
  47. Reul JM, de Kloet ER (1985) Two receptor systems for corticosterone in rat brain: microdistribution and differential occupation. Endocrinology. 117(6):2505–2511CrossRefGoogle Scholar
  48. Sacta MA, Chinenov Y, Rogatsky I (2016) Glucocorticoid signaling: an update from a genomic perspective. Annu Rev Physiol 78:155–180CrossRefGoogle Scholar
  49. Slezak M, Korostynski M, Gieryk A, Golda S, Dzbek J, Piechota M, Wlazlo E, Bilecki W, Przewlocki R (2013) Astrocytes are a neural target of morphine action via glucocorticoid receptor-dependent signaling. Glia 61(4):623–635CrossRefGoogle Scholar
  50. So AY, Chaivorapol C, Bolton EC, Li H, Yamamoto KR (2007) Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet 3:e94CrossRefGoogle Scholar
  51. Suetake I, Mishima Y, Kimura H, Lee YH, Goto Y, Takeshima H, Ikegami T, Tajima S (2011) Characterization of DNA-binding activity in the N-terminal domain of the DNA methyltransferase Dnmt3a. Biochem J 437(1):141–148CrossRefGoogle Scholar
  52. Surjit M, Ganti KP, Mukherji A, Ye T, Hua G, Metzger D et al (2011) Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145:224–241CrossRefGoogle Scholar
  53. Suzuki MM, Bird A (2008) DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet 9:465–476CrossRefGoogle Scholar
  54. Teicher MH, Tomoda A, Andersen SL (2006) Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable? Ann N Y Acad Sci 1071:313–323CrossRefGoogle Scholar
  55. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847–854CrossRefGoogle Scholar
  56. Wei D, Loeken MR (2014) Increased DNA methyltransferase 3b (Dnmt3b)-mediated CpG island methylation stimulated by oxidative stress inhibits expression of a gene required for neural tube and neural crest development in diabetic pregnancy. Diabetes 63(10):3512–3522CrossRefGoogle Scholar
  57. Wiley JW, Higgings GA, Athey BD (2016) Stress and glucocorticoid receptor transcriptional programming in time and space: implications for the brain-gut axis. Neurogastroenterol Motil 28(1):12–25CrossRefGoogle Scholar
  58. Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T et al (2014) A comparative encyclopedia of DNA elements in the mouse genome. Nature. 515:355–364CrossRefGoogle Scholar
  59. Zhu H, Wang G, Qian J (2016) Transcription factors as readers and effectors of DNA methylation. Nat Rev Genet 17:551–565CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Institute of Biomedicine and Translational MedicineUniversity of TartuTartuEstonia
  2. 2.Department of Human Biology and Genetics, Institute of Biomedicine and Translational MedicineUniversity of TartuTartuEstonia
  3. 3.Institute of Chemistry and BiotechnologyTallinn University of TechnologyTallinnEstonia
  4. 4.Department of Biomolecular SciencesWeizmann Institute of ScienceRehovotIsrael

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