Epigenetics of suicidal behavior

Suicide is the second leading cause of death among young people and therefore being a serious global problem worldwide. The study of genetic and epigenetic factors in the development of suicidal behavior plays an important role in the development of advanced methods of diagnosis and treatment of this pathology. The role of hereditary factors in the development of suicidal behavior is estimated at 30–55 %, with a pronounced comorbidity with other psychopathologies. The study of genetic liability to suicidal behavior is based on molecular-genetic methods including association and linkage analyses, chip gene expression arrays, and genome-wide association studies. Published data identified multiple genes including those involved in the functioning of serotonergic (SLC6A4, TPH, 5-HT1A), hypothalamic-pituitary-adrenal systems (FKBP5) and polyamines (SAT and OATL1) associated with suicidal behavior. However, the diversity of interacting genetic loci complicates the interpretation of the development of a complex phenotype of pathology and prevents the association from being detected. To solve this problem and interpret the missing relationship between the environment and the genome, promising results were obtained from a study of epigenetic factors, which affected the expression of a number of candidate genes involved in brain functioning in suicidal behavior. The analysis of a brain obtained from suicide victims, representing a unique tool for the analysis of modified genomic processes, revealed a wide range of reprogramming patterns of DNA methylation in promoters of the genes of polyamine (OAZ1, OAZ2, AMD1, ARG2, SKA2), serotonergic (SLC6A4) and GABAergic (GABRA1) systems, HPA-axis (GR, NR3C1), tyrosine kinase (TrkB) receptors, brain-derived neurotrophic factor (BDNF). The role of histone modifications in distinct genes (Cx30, Cx43, TrkB.T1) and the expression of specific long noncoding RNAs and microRNAs in the development of suicidal behavior, which is promising for the development of diagnostic algorithms and target therapy, is discussed.

1. Almeida D., Turecki G. A slice of the suicidal brain: what have postmortem molecular studies taught us? Curr. Psychiatry Rep. 2016;18:98.

2. Bach H., Arango V. Ch. 2. Neuroanatomy of Serotonergic Abnormalities in Suicide. In: Dwivedi Y. (Ed.) The Neurobiological Basis of Suicide. (Ser. Frontiers in Neuroscience). Boca Raton (FL): CRC Press/Taylor & Francis, 2012.

3. Bani-Fatemi A., Howe A.S., De Luca V. Epigenetic studies of suicidal behavior. Neurocase. 2015;21:134-143.

4. Burns S.B., Szyszkowicz J.K., Luheshi G.N., Lutz P.E., Turecki G. Plasticity of the epigenome during early-life stress. Semin. Cell. Dev. Biol. 2018;77:115-132.

5. Chandley M.J., Ordway G.A. Ch. 3. Noradrenergic Dysfunction in Depression and Sicide. In: Dwivedi Y. (Ed.) The Neurobiological Basis of Suicide. (Ser. Frontiers in Neuroscience). Boca Raton (FL): CRC Press/Taylor & Francis, 2012.

6. Cui X., Niu W., Kong L., He M., Jiang K., Chen S., Zhong A., Li W., Lu J., Zhang L. Long noncoding RNA expression in peripheral blood mononuclear cells and suicide risk in Chinese patients with major depressive disorder. Brain Behav. 2017;7:e00711.

7. Deng B., Cheng X., Li H., Qin J., Tian M., Jin G. Microarray expression profiling in the denervated hippocampus identified long noncoding RNAs functionally involved in neurogenesis. BMC Mol. Biol. 2017;18(1):15.

8. Dwivedi Y. MicroRNAs in depression and suicide: recent insights and future perspectives. J. Affect. Disord. 2018;240:146-154.

9. Emanuele E. The histone deacetylase inhibitor FK228 may have therapeutic usefulness to prevent suicidal behavior via upregulation of the guanosine triphosphatase Rap-1. Med. Hypotheses. 2007;68:451-452.

10. Ernst C., Chen E.S., Turecki G. Histone methylation and decreased expression of TrkB.T1 in orbital frontal cortex of suicide completers. Mol. Psychiatry. 2009a;14:830-832.

11. Ernst C., Deleva V., Deng X., Sequeira A., Pomarenski A., Klempan T., Ernst N., Quirion R., Gratton A., Szyf M., Turecki G. Alternative splicing, methylation state, and expression profile of tropomyosin-related kinase B in the frontal cortex of suicide completers. Arch. Gen. Psychiatry. 2009b;66:22-32.

12. Fanelli G., Serretti A. The influence of the serotonin transporter gene 5-HTTLPR polymorphism on suicidal behaviors: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2018;88:375-387.

13. Feng G., Leem Y.E., Levin H.L. Transposon integration enhances expression of stress response genes. Nucleic Acids Res. 2013;41(2):775-789.

14. Fiori L.M., Gross J.A., Turecki G. Effects of histone modifications on increased expression of polyamine biosynthetic genes in suicide. Int. J. Neuropsychopharmacol. 2012;15:1161-1166.

15. Fiori L.M., Turecki G. Epigenetic regulation of spermidine/spermine N1-acetyltransferase (SAT1) in suicide. J. Psychiatr. Res. 2011;45:1229-1235.

16. Fiori L.M., Wanner B., Jomphe V., Croteau J., Vitaro F., Tremblay R.E., Bureau A., Turecki G. Association of polyaminergic loci with anxiety, mood disorders, and attempted suicide. PLoS One. 2010;5:e15146.

17. Fudalej S., Kopera M., Wolynczyk-Gmaj D., Fudalej M., Krajewski P., Wasilewska K., Szymanski K., Chojnicka I., Podgorska A., Wojnar M., Ploski R. Association between FKBP5 functional polymorphisms and completed suicide. Neuropsychobiology. 2015;72:126-131.

18. Gross J.A., Fiori L.M., Labonte B., Lopez J.P., Turecki G. Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide. J. Psychiatr. Res. 2013;47:513519.

19. Guintivano J., Brown T., Newcomer A., Jones M., Cox O., Maher B.S., Eaton W.W., Payne J.L., Wilcox H.C., Kaminsky Z.A. Identification and replication of a combined epigenetic and genetic biomarker predicting suicide and suicidal behaviors. Am. J. Psychiatry. 2014;171:1287-1296.

20. Jeremian R., Chen Y.A., De Luca V., Vincent J.B., Kennedy J.L., Zai C.C., Strauss J. Investigation of correlations between DNA methylation, suicidal behavior and aging. Bipolar Disord. 2017;19:32-40.

21. Jiménez-Treviño L., Saiz P.A., Garcia-Portilla M.P., Blasco-Fontecilla H., Carli V., Iosue M., Jaussent I., López-Castroman J., Vaguero-Lorenzo C., Sarchiapone M., Baca-Garcia E., Courtet P., Bobes J. 5-HTTLPR-brain-derived neurotorophic factor (BDNF) gene interactions and early adverse life events effect on impulsivity in suicide attempters. World J. Biol. Psychiatry. Epub Oct 2017; Publ. 2019;20(2):137-149.

22. Johnson R., Guigo R. The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA. 2014;20(7):959-976.

23. Joiner T.E. Why People Die by Suicide. Cambridge, MA: Harvard Univ. Press, 2005.

24. Kang H.J., Bae K.Y., Kim S.W., Shin I.S., Hong Y.J., Ahn Y., Jeong M.H., Yoon J.S., Kim J.M. BDNF methylation and suicidal ideation in patients with acute coronary syndrome. Psychiatry Investig. 2018;15(11):1094-1097. DOI 10.30773/pi.2018.09.20.

25. Kang H.J., Kim J.M., Lee J.Y., Kim S.Y., Bae K.Y., Kim S.W., Shin I.S., Kim H.R., Shin M.G., Yoon J.S. BDNF promoter methylation and suicidal behavior in depressive patients. J. Affect. Disord. 2013;151:679-685.

26. Kapusta A., Feschotte C. Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implications. Trends Genet. 2014;30(10):439-452.

27. Keller S., Sarchiapone M., Zarrilli F., Tomaiuolo R., Carli V., Angrisano T., Videtic A., Amato F., Pero R., di Giannantonio M., Losue M., Lembo F., Castaldo G., Chiarriotti L. TrkB gene expression and DNA methylation state in Wernicke area does not associate with suicidal behavior. J. Affect. Disord. 2011;135:400-404.

28. Keller S., Sarchiapone M., Zarrilli F., Videtic A., Ferraro A., Carli V., Sacchetti S., Lembo F., Angiolillo A., Jovanovic N., Pisanti F., Tomaiuolo R., Monticelli A., Balazic J., Roy A., Marusic A., Cocozza S., Fusco A., Bruni C.B., Castaldo G., Chiariotti L. Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch. Gen. Psychiatry. 2010;67:258-267.

29. Kim J.M., Kang H.J., Bae K.Y., Kim S.W., Shin I.S., Kim H.R., Shin M.G., Yoon J.S. Association of BDNF promoter methylation and genotype with suicidal ideation in elderly Koreans. Am. J. Geriatr. Psychiatry. 2014;22:989-996.

30. Lopez J.P., Fiori L.M., Gross J.A., Labonte B., Yerko V., Mechawar N., Turecki G. Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int. J. Neuropsychopahrmacol. 2014;17:23-32.

31. Lu X., Sachs F., Ramsay L., Jacques P.E., Goke J., Bourque G., Ng H.H. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat. Struct. Mol. Biol. 2014;21(4):423-425.

32. Ludwig B., Roy B., Wang Q., Birur B., Dwivedi Y. The life span model of suicide and its neurobiological foundation. Front. Neurosci. 2017;11:74.

33. Lutz P.E., Mechawar N., Turecki G. Neuropathology of suicide: recent findings and future directions. Mol. Psychiatry. 2017;22:1395-1412.

34. Mann J.J., Currier D.M. Stress, genetics and epigenetic effects on the neurobiology of suicidal behavior and depression. Eur. Psychiatry. 2010;25:268-271.

35. Mann J.J., Waternaux C., Haas G.L., Malone K.M. Toward a clinical model of suicidal behavior in psychiatric patients. Am. J. Psychiatry. 1999;156(2):181-189.

36. Maussion G., Yang J., Suderman M., Diallo A., Nagy C., Arnovitz M., Mechawar N., Turecki G. Functional DNA methylation in a transcript specific 3′UTR region of TrkB associates with suicide. Epigenetics. 2014;9:1061-1070.

37. Maussion G., Yang J., Yerko V., Barker P., Mechawar N., Ernst C., Turecki G. Regulation of a truncated form of tropomyosin-related kinase B (TrkB) by Hsa-miR-185* in frontal cortex of suicide completers. PLoS One. 2012;7:e39301.

38. McGowan P.O., Sasaki A., D’Alessio A.C., Dymov S., Labonte B., Szyf M., Turecki G., Meaney M.J. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat. Neurosci. 2009;12:342-348.

39. Mustafi R.N., Khusnutdinova E.K. Non-coding parts of genomes as the basis of epigenetic heredity. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2017;21(6):742-749. DOI 10.18699/VJ17.30-о. (in Russian)

40. Nagy C., Torres-Platas S.G., Mechawar N., Turecki G. Repression of astrocytic connexins in cortical and subcortical brain regions and prefrontal enrichment of H3K9me3 in depression and suicide. Int. J. Neuropsychopharmacol. 2017;20:50-57.

41. Nock M.K., Green J.G., Hwang I., McLaughlin K.A., Sampson N.A., Zaslavsky A.M., Kessler R.C. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents: results from the National Comorbidity Survey Replication Adolescent Supplement. JAMA Psychiatry. 2013;70:300-310.

42. Olié E., Courtet P. Genetics and epigenetics of suicidal behaviors. Biol. Aujourd’hui. 2017;211:93-96.

43. Pandey G.N., Rizavi H.S., Zhang H., Bhaumik R., Ren X. The expression of the suicide-associated gene SKA2 is decreased in the prefrontal cortex of suicide victims but not of nonsuicidal patients. Int. J. Neuropsychopharmacol. 2016;19(8):1-10. DOI 10.1093/ijnp/pyw015.

44. Poulter M.O., Du L., Weaver I.C., Palkovits M., Faludi G., Merali Z., Szyf M., Anisman H. GABA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol. Psychiatry. 2008;64: 645-652.

45. Punzi G., Ursini G., Shin J.H., Kleinman J.E., Hyde T.M., Weinberger D.R. Increased expression of MARCKS in post-mortem brain of violent suicide completers is related to transcription of a long, noncoding, antisense RNA. Mol. Psychiatry. 2014;19:1057-1059.

46. Roy B., Dwivedi Y. Understanding epigenetic architecture of suicide neurology: a critical perspective. Neurosci. Biobehav. Rev. 2017;72:10-27.

47. Roy B., Dwivedi Y. Understanding the neuroepigenetic constituents of suicide brain. Prog. Mol. Biol. Transl. Sci. 2018;157:233-262.

48. Roy B., Wang Q., Palkovits M., Faludi G., Dwivedi Y. Altered miRNA expression network in locus coeruleus of depressed suicide subjects. Sci. Rep. 2017;7:4387.

49. Sadeh N., Wolf E.J., Logue M.W., Hayes J.P., Stone A., Griffin L.M., Schichman S.A., Miller M.W. Epigenetic variation at SKA2 predicts suicide phenotypes and internalizing psychopathology. Depress. Anxiety. 2016;33:308-315.

50. Serafini G., Pompili M., Innamorati M., Giordano G., Montebovi F., Sher L., Dwivedi Y., Girardi P. The role of microRNAs in synaptic plasticity, major affective disorders and suicidal behavior. Neurosci. Res. 2012;73:179-190.

51. Schneider E., El Hajj N., Muller F., Navarro B., Haaf T. Epigenetic dysregulation in the prefrontal cortex of suicide completers. Cytogenet. Genome Res. 2015;146:19-27.

52. Smalheiser N.R., Lugli G., Rizavi H.S., Torvik V.I., Turecki G., Dwivedi Y. MicroRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One. 2012;7:e33201.

53. Tsai S.J., Hong C.J., Liou Y.J. Recent molecular genetic studies and methodological issues in suicide research. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2011;35:809-917.

54. Turecki G. Epigenetics and suicidal behavior research pathways. Am. J. Prev. Med. 2014;47:144-151.

55. van Heeringen K., Mann J.J. The neurobiology of suicid. Lancet Psychiatry. 2014;1:63-72.

56. Vojta A., Dobrinic P., Tadic V., Bockor L., Korac P., Julg B., Klasic M., Zoldos V. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res. 2016;44:56155628.

57. Wang Q., Roy B., Turecki G., Shlton R.C., Dwivedi Y. Role of complex epigenetic switching in tumor necrosis factor-α upregulation in the prefrontal cortex of suicide subjects. Am. J. Psychiatry. 2018;175:262-274.

58. Wheeler B.S. Small RNAs, big impact: small RNA pathways in transposon control and their effect on the host stress response. Chromosome Res. 2013;21:587-600.

59. Zhou Y., Lutz P.E., Wang Y.C., Ragoussis J., Turecki G. Global long non-coding RNA expression in the rostral anterior cingulated cortex of depressed suicides. Transl. Psychiatry. 2018;8:224.