Epigenetische Veränderungen bei affektiven Störungen

Zusammenfassung

Veränderungen der epigenetischen Kontrolle der Genregulation durch DNA-Methylierung, Histonmodifikationen und Chromatinremodelling werden zunehmend auch im Rahmen psychischer Erkrankungen untersucht. Befunde aus den vergangenen zehn Jahren legen nahe, dass epigenetischen Veränderungen eine wesentliche Rolle in der biologischen Grundlage affektiver Störungen zukommt. Dabei können über epigenetische Einflüsse intrauterine und frühkindliche Erfahrungen gespeichert werden und die Vulnerabilität für affektive Störungen erhöhen. Aber auch während der akuten Erkrankung können epigenetische Mechanismen das biologische Substrat aufrechterhaltender Bedingungen sein. Durch die Kenntnis epigenetischer Prozesse im Rahmen der Depression sind in den nächsten Jahren Fortschritte in Therapie und Diagnostik dieser schweren psychischen Erkrankungen zu erwarten.

Summary

Changes in the epigenetic control of the regulation of genes through DNA methylation, modification of histone proteins and chromatine remodelling are increasingly recognized in their fundamental role in psychiatric disorders. Research findings from the last decade show that epigenetic dysregulation plays a major role in the biological underpinnings of affective disorders. Intrauterine as well as early developmental experiences can be transmitted into vulnerability towards the disorder by epigenetic means. But also during the episodes of depression, epigenetic mechanisms may be the substrate of maintaining factors. Investigating the epigenetic underpinning of the disorder will help to advance understanding, diagnostics and therapy of this devastating illness.

Schlüsselwörter

Depression - Epigenetik - DNA-Methylierung

Keywords

Depression - epigenetics - DNA methylation

• Literatur

• 1 Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. Canadian Medical Association Journal 2006; 174 (Suppl. 03) 341-8.
• 2 Muschler MA, Hillemacher T, Kraus C, Kornhuber J, Bleich S, Frieling H. DNA methylation of the POMC gene promoter is associated with craving in alcohol dependence. J Neural Transm 2010; 117 (Suppl. 04) 513-9.
• 3 Frieling H. et al. Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry 2007; 12 (Suppl. 03) 229-30.
• 4 Grayson D. et al. Reelin promoter hypermethylation in schizophrenia. Proceedings of the National Academy of Sciences 2005; 102 (Suppl. 26) 9341-6.
• 5 Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H. One-carbon metabolism and schizophrenia: current challenges and future directions. Trends Mol Med 2009; 15 (Suppl. 12) 562-70.
• 6 Weaver ICG. et al. Reversal of maternal programming of stress responses in adult offspring through methyl upplementation: alterning epigenetic marking later in ife. J Neurosci 2005; 25 (Suppl. 47) 11045-54.
• 7 Weaver ICG, Meaney MJ, Szyf M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci U S A 2006; 103 (Suppl. 09) 3480-5.
• 8 Szyf M, Weaver ICG, Champagne FA, Diorio J, Meaney MJ. Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Frontiers in Neuroendocrinology 2005; 26 3–4 139-62.
• 9 Murgatroyd C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 2009; 12 (Suppl. 12) 1559-66.
• 10 Roth TL, Lubin FD, Funk AJ, Sweatt JD. Lasting epi-genetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 2009; 65 (Suppl. 09) 760-9.
• 11 McGowan PO. et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009; 12 (Suppl. 03) 342-8.
• 12 Alt SR. et al. Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed. Psycho-neuroendocrinology 2010; 35 (Suppl. 04) 544-56.
• 13 Moser D, Molitor A, Kumsta R, Tatschner T, Riederer P, Meyer J. The glucocorticoid receptor gene exon 1-F promoter is not methylated at the NGFI-A binding site in human hippocampus. World Journal of Biological Psychiatry 2007; 8 (Suppl. 04) 262-8.
• 14 Beach SRH, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at SLC6A4 is linked to family history of child abuse: An examination of the Iowa Adoptee sample. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2010; 153B (Suppl. 02) 710-3.
• 15 Beach SRH, Brody GH, Todorov AA, Gunter TD, Philibert RA. Methylation at 5HTT mediates the impact of child sex abuse on women’s antisocial behavior: an examination of the Iowa adoptee sample. Psychosomatic Medicine 2011; 73 (Suppl. 01) 83-7.
• 16 Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2008; 147B (Suppl. 05) 543-9.
• 17 van Ijzendoorn MH, Caspers K, Bakermans-Kranenburg MJ, Beach SRH, Philibert R. Methylation matters: interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biol Psychiatry 2010; 68 (Suppl. 05) 405-7.
• 18 Devlin AM, Brain U, Austin J, Oberlander TF. Prenatal exposure to maternal depressed mood and the C677T variant affect SLC6A4 methylation in infants at birth. PLoS ONE 2010; 5 (Suppl. 08) e12201.
• 19 Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 2008; 3 (Suppl. 02) 97-106.
• 20 Covington HE. et al. Antidepressant actions of histone deacetylase inhibitors. J Neurosci 2009; 29 (Suppl. 37) 11451-60.
• 21 Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 2006; 9 (Suppl. 04) 519-25.
• 22 Tsankova NM, Kumar A, Nestler EJ. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 2004; 24 (Suppl. 24) 5603-10.
• 23 Poulter MO. et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 2008; 64 (Suppl. 08) 645-52.
• 24 McGowan PO. et al. Promoter-wide hypermethylation of the ribosomal RNA gene promoter in the suicide brain. PLoS ONE 2008; 3 (Suppl. 05) e2085.
• 25 Ernst C. et al. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch Gen Psychiatry 2009; 66 (Suppl. 01) 22-32.
• 26 Uddin M, Koenen KC, Aiello AE, Wildman DE, de los Santos R, Galea S. Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. Psychol Med 2011; 41 (Suppl. 05) 997-1007.
• 27 Gregory SG. et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 2009; 7: 62.