Original Article | Published:

The ESC/E(Z) complex, an effector of response to ovarian steroids, manifests an intrinsic difference in cells from women with premenstrual dysphoric disorder

Molecular Psychiatry volume 22, pages 11721184 (2017) | Download Citation

Abstract

Clinical evidence suggests that mood and behavioral symptoms in premenstrual dysphoric disorder (PMDD), a common, recently recognized, psychiatric condition among women, reflect abnormal responsivity to ovarian steroids. This differential sensitivity could be due to an unrecognized aspect of hormonal signaling or a difference in cellular response. In this study, lymphoblastoid cell line cultures (LCLs) from women with PMDD and asymptomatic controls were compared via whole-transcriptome sequencing (RNA-seq) during untreated (ovarian steroid-free) conditions and following hormone treatment. The women with PMDD manifested ovarian steroid-triggered behavioral sensitivity during a hormone suppression and addback clinical trial, and controls did not, leading us to hypothesize that women with PMDD might differ in their cellular response to ovarian steroids. In untreated LCLs, our results overall suggest a divergence between mRNA (for example, gene transcription) and protein (for example, RNA translation in proteins) for the same genes. Pathway analysis of the LCL transcriptome revealed, among others, over-expression of ESC/E(Z) complex genes (an ovarian steroid-regulated gene silencing complex) in untreated LCLs from women with PMDD, with more than half of these genes over-expressed as compared with the controls, and with significant effects for MTF2, PHF19 and SIRT1 (P<0.05). RNA and protein expression of the 13 ESC/E(Z) complex genes were individually quantitated. This pattern of increased ESC/E(Z) mRNA expression was confirmed in a larger cohort by qRT-PCR. In contrast, protein expression of ESC/E(Z) genes was decreased in untreated PMDD LCLs with MTF2, PHF19 and SIRT1 all significantly decreased (P<0.05). Finally, mRNA expression of several ESC/E(Z) complex genes were increased by progesterone in controls only, and decreased by estradiol in PMDD LCLs. These findings demonstrate that LCLs from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated condition and in response to ovarian hormones. Dysregulation of ESC/E(Z) complex function could contribute to PMDD.

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References

  1. 1.

    American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders, 5th edn. American Psychiatric Association: Arlington, VA, USA, 2013.

  2. 2.

    , , . Premenstrual syndrome. Lancet 2008; 371: 1200–1210.

  3. 3.

    , , , , , et al. Premenstrual dysphoric disorder: evidence for a new category for DSM-5. Am J Psychiatry 2012; 169: 465–475.

  4. 4.

    , . Premenstrual dysphoric disorder: burden of illness and treatment update. J Psychiatry Neurosci 2008; 33: 291–301.

  5. 5.

    , , , . The prevalence, impairment, impact, and burden of premenstrual dysphoric disorder (PMS/PMDD). Psychoneuroendocrinology 2003; 28: 1–23.

  6. 6.

    , , , , . Reproductive steroid regulation of mood and behavior. Compr Physiol 2016; 13: 1135–1160.

  7. 7.

    , , . Spontaneous anovulation causing disappearance of cyclical symptoms in women with the premenstrual syndrome. Acta Endocrinol 1991; 125: 132–137.

  8. 8.

    , , , , . Differential behavioral effects of gonadal steroids in women with and in those without premenstrual syndrome. N Engl J Med 1998; 338: 209–216.

  9. 9.

    , , , . Premenstrual syndrome and related hormonal changes: long-acting gonadotropin releasing hormone agonist treatment. J Reprod Med 1993; 38: 864–870.

  10. 10.

    , , , , . Efficacy of depot leuprolide in premenstrual syndrome: effect of symptom severity and type in a controlled trial. Obstet Gynecol 1994; 84: 779–786.

  11. 11.

    , , , . Gonadotropin-releasing hormone agonist in treatment of premenstrual symptoms: with and without comorbidity of depression: a pilot study. J Clin Psychiatry 1993; 54: 192–195.

  12. 12.

    , . Ovarian suppression with the gonadotrophin-releasing hormone agonist goserelin (Zoladex) in management of the premenstrual tension syndrome. Hum Reprod 1994; 9: 1058–1063.

  13. 13.

    , , , , . Buserelin in premenstrual syndrome. Gynecol Endocrinol 1992; 6: 57–64.

  14. 14.

    , , , , , et al. Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc Natl Acad Sci USA 2005; 102: 16060–16065.

  15. 15.

    , , , , , et al. Hippocampal structural changes across the menstrual cycle. Hippocampus 2008; 18: 985–988.

  16. 16.

    , , , , , et al. Toward a functional neuroanatomy of premenstrual dysphoric disorder. J Affect Disord 2007; 108: 87–94.

  17. 17.

    , , , , , et al. Abnormalities of dorsolateral prefrontal function in women with premenstrual dysphoric disorder: a multimodal neuroimaging study. Am J Psychiatry 2013; 170: 305–314.

  18. 18.

    , . Menstrual cycle modulation of medial temporal activity evoked by negative emotion. Neuroimage 2010; 53: 1286–1293.

  19. 19.

    , , , , . Sex differences in stress response circuitry activation dependent on female hormonal cycle. J Neurosci 2010; 30: 431–438.

  20. 20.

    , , , , . Premenstrual dysphoric disorder and prefrontal reactivity during anticipation of emotional stimuli. Eur Neuropsychopharmacol 2013; 23: 1474–1483.

  21. 21.

    , . Menstrual cycle influence on cognitive function and emotion processing-from a reproductive perspective. Front Neurosci 2014; 8: 380.

  22. 22.

    , , , , , . Menstrual cycle phase modulates reward-related neural function in women. Proc Natl Acad Sci USA 2007; 104: 2465–2470.

  23. 23.

    , , , , , et al. Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women. Proc Natl Acad Sci USA 1997; 94: 8836–8841.

  24. 24.

    , , , , . Emotional and cognitive functional imaging of estrogen and progesterone effects in the female human brain: a systematic review. Psychoneuroendocrinology 2014; 50: 28–52.

  25. 25.

    , , , , , et al. Effects of estradiol withdrawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015; 72: 714–726.

  26. 26.

    , , , , , . Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 2000; 157: 924–930.

  27. 27.

    , , , , , et al. Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling. Psychol Med 2014; 44: 2309–2322.

  28. 28.

    , , , , . Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. Mol Psychiatry 2014; 19: 560–567.

  29. 29.

    , , . Lymphocytes as a neural probe: potential for studying psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 559–576.

  30. 30.

    , . The peripheral-blood transcriptome: new insights into disease and risk assessment. Trends Mol Med 2007; 13: 422–432.

  31. 31.

    , , , , . Exploration of neuroendocrine and immune gene expression in peripheral blood mononuclear cells. Brain Res Mol Brain Res 2004; 129: 193–197.

  32. 32.

    , , . Utility of lymphoblastoid cell lines. J Neurosci Res 2009; 87: 1953–1959.

  33. 33.

    , , , , . Feasibility of using cryopreserved lymphoblastoid cells to diagnose some lysosomal storage diseases. Cell Prolif 2010; 43: 164–169.

  34. 34.

    , . What can we learn about depression from gene expression in peripheral tissues? Biol Psychiatry 2015; 77: 207–209.

  35. 35.

    , , . Molecular assessment of depression from mRNAs in the peripheral leukocytes. Ann Med 2008; 40: 336–342.

  36. 36.

    , , . Use of peripheral blood transcriptome biomarkers for epilepsy prediction. Neurosci Lett 2011; 497: 213–217.

  37. 37.

    , , . On the outside, looking in: a review and evaluation of the comparability of blood and brain ‘-omes’. Am J Med Genet B Neuropsychiatr Genet 2013; 162B: 595–603.

  38. 38.

    American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Association: Washington, DC, USA, 1994.

  39. 39.

    , , , , . Prospective assessment of menstrually related mood disorders. Am J Psychiatry 1984; 141: 684–686.

  40. 40.

    , , , . Premenstrual changes: patterns and correlates of daily ratings. J Affect Disord 1986; 10: 127–135.

  41. 41.

    , , , . Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-IP). Biometrics Research, New York State Psychiatric Institute: New York, NY, USA, 2002.

  42. 42.

    , , , , , et al. Clinical diagnosis criteria for premenstrual syndrome and guidelines for their quantification for research studies. Gynecol Endocrinol 2007; 23: 123–130.

  43. 43.

    . The diagnosis of premenstrual syndromes and premenstrual dysphoric disorder - clinical procedures and research perspectives. Gynecol Endocrinol 2004; 19: 320–334.

  44. 44.

    , , . Gonadotropin-releasing hormone agonist in the treatment of premenstrual symptoms with and without ongoing dysphoria: a controlled study. Psychopharmacol Bull 1997; 33: 303–309.

  45. 45.

    , , , , , . Effects of pharmacologically-induced hypogonadism on mood and behavior in healthy young women. Am J Psychiatry 2013; 170: 426–433.

  46. 46.

    , , , , , et al. An efficient method for the rapid establishment of Epstein-Barr virus immortalization of human B lymphocytes. Cell Prolif 2003; 36: 191–197.

  47. 47.

    . Statistical methods for pathway analysis of genome-wide data for association with complex genetic traits. Adv Genet 2010; 72: 141–179.

  48. 48.

    , , , , , et al. Isoelectric focusing technology quantifies protein signaling in 25 cells. Proc Natl Acad Sci USA 2006; 103: 16153–16158.

  49. 49.

    , , , , , . Histone methyltransferase EZH2 is transcriptionally induced by estradiol as well as estrogenic endocrine disruptors bisphenol-A and diethylstilbestrol. J Mol Biol 2014; 426: 3426–3441.

  50. 50.

    , , , , , et al. Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2. Cell Rep 2013; 3: 411–426.

  51. 51.

    , , , , , . Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol 2010; 24: 993–1006.

  52. 52.

    , , , , , et al. Progesterone receptor activation downregulates GATA3 by transcriptional repression and increased protein turnover promoting breast tumor growth. Breast Cancer Res 2014; 16: 491.

  53. 53.

    , , , , . Changes in the transcriptome of the human endometrial Ishikawa cancer cell line induced by estrogen, progesterone, tamoxifen, and mifepristone (RU486) as detected by RNA-sequencing. PLoS ONE 2013; 8: e68907.

  54. 54.

    , , , , , et al. Upregulation of SIRT1 by 17beta-estradiol depends on ubiquitin-proteasome degradation of PPAR-gamma mediated by NEDD4-1. Protein Cell 2013; 4: 310–321.

  55. 55.

    , , . Sirtuin 1 (SIRT1) and steroid hormone receptor activity in cancer. J Endocrinol 2012; 213: 37–48.

  56. 56.

    , , , , , et al. Systematic dissection of the mechanisms underlying progesterone receptor downregulation in endometrial cancer. Oncotarget 2014; 5: 9783–9797.

  57. 57.

    , , , , , et al. EZH2 regulates the transcription of estrogen-responsive genes through association with REA, an estrogen receptor corepressor. Breast Caner Res Treat 2008; 107: 235–242.

  58. 58.

    , , , , , . Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res Bull 2013; 97: 69–80.

  59. 59.

    , . The polycomb complex PRC2 and its mark in life. Nature 2011; 469: 343–349.

  60. 60.

    , . Transcriptional regulation by polycomb group proteins. Nat Struct Mol Biol 2013; 20: 1147–1155.

  61. 61.

    , . Mechanisms of polycomb gene silencing: knowns and unknowns. Nat Rev Mol Cell Biol 2009; 10: 697–708.

  62. 62.

    , . Neurosteroid, GABAergic and hypothalamic pituitary adrenal (HPA) axis regulation: what is the current state of knowledge in humans? Psychopharmacology 2014; 231: 3619–3634.

  63. 63.

    , , , , , . Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity. BMC Pharmacol Toxicol 2013; 14: 37.

  64. 64.

    , , , , , et al. Cortical γ-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study. Arch Gen Psychiatry 2002; 59: 851–858.

  65. 65.

    , , , , . Abnormal luteal phase excitability of the motor cortex in women with premenstrual syndrome. Biol Psychiatry 2003; 54: 757–762.

  66. 66.

    , , . Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology 2014; 231: 3557–3567.

  67. 67.

    , , , , . Regulation of hippocampal H3 histone methylation by acute and chronic stress. Proc Natl Acad Sci USA 2009; 106: 20912–20917.

  68. 68.

    , . Balancing histone methylation activities in psychiatric disorders. Trends Mol Med 2011; 17: 372–379.

  69. 69.

    , , . Histone deacetylases and mood disorders: epigenetic programming in gene-environment interactions. CNS Neurosci Ther 2011; 17: 699–704.

  70. 70.

    , , . Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Mol Psychiatry 2009; 14: 830–832.

  71. 71.

    , , , , , et al. SIRT1 gene is associated with major depressive disorder in the Japanese population. J Affect Disord 2010; 126: 167–173.

  72. 72.

    , , , , , et al. Social defeat induces changes in histone acetylation and expression of histone modifying enzymes in the ventral hippocampus, prefrontal cortex, and dorsal raphe nucleus. Neuroscience 2014; 264: 88–98.

  73. 73.

    , , , , , et al. Genome-wide analysis of chromatin regulation by cocaine reveals a role for sirtuins. Neuron 2009; 62: 335–348.

  74. 74.

    , , , , , . Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006; 9: 519–525.

  75. 75.

    , , , , , et al. The polycomb group protein EZH2 is required for mammalian circadian clock function. J Biol Chem 2006; 281: 21209–21215.

  76. 76.

    , , , , , et al. l-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA 2013; 110: 4804–4809.

  77. 77.

    , , , , , et al. Coordinated regulation of dendrite arborization by epigenetic factors CDYL and EZH2. J Neurosci 2014; 34: 4494–4508.

  78. 78.

    , , , , , . Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc Natl Acad Sci USA 2010; 107: 15957–15962.

  79. 79.

    , , , , , et al. SirT1 mediates hyperbaric oxygen preconditioning-induced ischemic tolerance in rat brain. J Cereb Blood Flow Metab 2013; 33: 396–406.

  80. 80.

    , , , , , et al. SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell 2011; 147: 1459–1472.

  81. 81.

    CONVERGE Consortium. Sparse whole-genome sequencing identifies two loci for major depressive disorder. Nature 2015; 523: 588–591.

  82. 82.

    , . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

  83. 83.

    . The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 2015; 20: 32–47.

  84. 84.

    , . The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol 2016; 16: 22–34.

  85. 85.

    , , , , , et al. Association of inflammation markers with menstrual symptom severity and premenstrual syndrome in young women. Hum Reprod 2014; 29: 1987–1994.

  86. 86.

    , , . The association of inflammation with premenstrual symptoms. J Womens Health 2016; 25: 865–874.

  87. 87.

    , , , , , et al. Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biol Psychiatry 2007; 62: 925–933.

  88. 88.

    , . SIRT1 (sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae). Atlas Genet Cytogenet Oncol Haematol 2010; 14: 1152–1156.

  89. 89.

    , . Sorting out functions of sirtuins in cancer. Oncogene 2014; 33: 1609–1620.

  90. 90.

    , , , , , et al. Mammalian polycomb-like Pcl2/Mtf2 is a novel regulatory component of PRC2 that can differentially modulate polycomb activity both at the Hox gene cluster and at Cdkn2a genes. Mol Cell Biol 2011; 31: 351–364.

  91. 91.

    , . A global view of transcriptional regulation by nuclear receptors: gene expression, factor localization, and DNA sequence analysis. Nucl Recept Signal 2008; 6: e005.

  92. 92.

    , . Hormone-regulated transcriptomes: lessons learned from estrogen signaling pathways in breast cancer cells. Mol Cell Endocrinol 2014; 382: 652–664.

  93. 93.

    , , . Time- and dose-dependent differential upregulation of three genes by 17 beta-estradiol in endothelial cells. J Appl Physiol (1985) 2002; 92: 1064–1073.

  94. 94.

    , , , , , et al. Progesterone receptors: form and function in brain. Front Neuroendocrinol 2008; 29: 313–339.

  95. 95.

    , , , , , et al. Differential responses of progesterone receptor membrane component-1 (Pgrmc1) and the classical progesterone receptor (Pgr) to 17β-estradiol and progesterone in hippocampal subregions that support synaptic remodeling and neurogenesis. Endocrinology 2012; 153: 759–769.

  96. 96.

    , . Neural progestin receptors and female sexual behavior. Neuroendocrinology 2012; 96: 152–161.

  97. 97.

    , . Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells. Neuroendocrinology 2012; 96: 162–171.

  98. 98.

    , , . Evidence for a genomic mechanism of action for progesterone receptor membrane component-1. Steroids 2012; 77: 1007–1012.

  99. 99.

    . Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol 2008; 29: 292–312.

  100. 100.

    , , , , , et al. Revisiting the roles of progesterone and allopregnanolone in the nervous system: resurgence of the progesterone receptors. Prog Neurobiol 2014; 113: 6–39.

  101. 101.

    , , , , . The Drosophila Polycomb Group proteins ESC and E(Z) are present in a complex containing the histone-binding protein p55 and the histone deacetylase RPD3. Development 2001; 128: 275–286.

  102. 102.

    , . Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 1999; 23: 474–478.

  103. 103.

    , , , , , . Genetic and environmental factors in the aetiology of menstrual, premenstrual and neurotic symptoms: a population-based twin study. Psychol Med 1992; 22: 85–100.

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Acknowledgements

We thank Cheryl Marietta, Longina Akhtar, Bani Mukhopadhyay and Elisa Moore of NIAAA for their technical assistance and expertise in conducting this study. We also thank Karla Thompson and Linda Schenkel of NIMH for their clinical support and data management, and Catherine Roca who initiated the PMDD genetics project and was responsible for collecting many of the samples employed in the replication sample for this study. Finally, we thank Dr. Shailaja Mani of Baylor College of Medicine for her guidance and consultation on this project. This work was written as part of Peter J. Schmidt’s official duties as a Government employee. This research was supported by the Intramural Research Program of the NIMH and NIAAA NIH; NIMH Protocols NCT00001259 and NCT00001322; and NIMH Project # MH002865; NIAAA Project # AA000301.

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Author notes

    • N Dubey
    •  & J F Hoffman

    These authors contributed equally to this work.

Affiliations

  1. Behavioral Endocrinology Branch, NIMH, IRP/NIH/HHS, Bethesda, MD, USA

    • N Dubey
    • , J F Hoffman
    • , P E Martinez
    •  & P J Schmidt
  2. Laboratory of Neurogenetics, NIAAA, Bethesda, MD, USA

    • K Schuebel
    • , Q Yuan
    •  & D Goldman
  3. Intramural Research Program on Reproductive and Adult Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHSS, Bethesda, MD, USA

    • L K Nieman
  4. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • D R Rubinow

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Correspondence to P J Schmidt.

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https://doi.org/10.1038/mp.2016.229

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