Methylation of the tryptophan hydroxylase‑2 gene is associated with mRNA expression in patients with major depression with suicide attempts

Zhang,Yuqi; Chang,Zaohuo; Chen,Jionghua; Ling,Yang; Liu,Xiaowei; Feng,Zhang; Chen,Caixia; Xia,Minghua; Zhao,Xingfu; Ying,Wang; Qing,Xu; Li,Guilin; Zhang,Changsong

doi:10.3892/mmr.2015.3748

Methylation of the tryptophan hydroxylase‑2 gene is associated with mRNA expression in patients with major depression with suicide attempts

Authors:
- Yuqi Zhang
- Zaohuo Chang
- Jionghua Chen
- Yang Ling
- Xiaowei Liu
- Zhang Feng
- Caixia Chen
- Minghua Xia
- Xingfu Zhao
- Wang Ying
- Xu Qing
- Guilin Li
- Changsong Zhang
View Affiliations

Affiliations: Department of Geriatric Psychiatry, Wuxi Psychiatric Hospital, Nanjing Medical University, Wuxi, Jiangsu 214151, P.R. China, Department of Brain, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, P.R. China, Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
Published online on: May 7, 2015 https://doi.org/10.3892/mmr.2015.3748
Pages: 3184-3190

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tryptophan hydroxylase‑2 (TPH2) contributes to alterations in the function of neuronal serotonin (5‑HT), which are associated with various psychopathologies, including major depressive disorder (MDD) or suicidal behavior. The methylation of a single CpG site in the promoter region of TPH2 affects gene expression. Suicide and MDD are strongly associated and genetic factors are at least partially responsible for the variability in suicide risk. The aim of the present study was to investigate whether variations in TPH2 methylation in peripheral blood samples may predispose patients with MDD to suicide attempts. TPH2 mRNA expression levels differed significantly between 50 patients with MDD who had attempted suicide (MDD + suicide group) and 75 control patients with MDD (MDD group); TPH2 expression levels were significantly decreased (P=0.0005) in the patients who had attempted suicide. Furthermore, the frequency of TPH2 methylation was 36.0% in the MDD + suicide group, while it was 13.0% in the MDD group. The results of the present study demonstrated that methylation in the promoter region of TPH2 significantly affected the mRNA expression levels of TPH2, thus suggesting that methylation of the TPH2 promoter may silence TPH2 mRNA expression in MDD patients with or without suicidal behavior. In addition, there was a significant correlation between the methylation status of the TPH2 promoter and depression, hopelessness and cognitive impairment in the MDD + suicide group. In conclusion, the present study demonstrated that TPH2 expression was regulated by DNA methylation of the TPH2 promoter region in patients with MDD.

View Figures

View References

1	Hawton K and van Heeringen K: Suicide. Lancet. 373:1372–1381. 2009. View Article : Google Scholar : PubMed/NCBI
2	McGirr A, Renaud J, Séguin M, Alda M and Turecki G: Course of major depressive disorder and suicide outcome: A psychological autopsy study. J Clin Psychiatry. 69:966–970. 2008. View Article : Google Scholar : PubMed/NCBI
3	Cavanagh JT, Carson AJ, Sharpe M and Lawrie SM: Psychological autopsy studies of suicide: A systematic review. Psychol Med. 33:395–405. 2003. View Article : Google Scholar : PubMed/NCBI
4	Pompili M, Innamorati M, Raja M, et al: Suicide risk in depression and bipolar disorder: Do impulsiveness-aggressiveness and pharmacotherapy predict suicidal intent? Neuropsychiatr Dis Treat. 4:247–255. 2008. View Article : Google Scholar : PubMed/NCBI
5	Matthes S, Mosienko V, Bashammakh S, Alenina N and Bader M: Tryptophan hydroxylase as novel target for the treatment of depressive disorders. Pharmacology. 85:95–109. 2010. View Article : Google Scholar : PubMed/NCBI
6	Chen GL and Miller GM: Advances in tryptophan hydroxylase-2 gene expression regulation: New insights into serotonin-stress interaction and clinical implications. Am J Med Genet B Neuropsychiatr Genet. 159B:152–171. 2012. View Article : Google Scholar : PubMed/NCBI
7	Must A, Tasa G, Lang A, et al: Variation in tryptophan hydroxylase-2 gene is not associated to male completed suicide in Estonian population. Neurosci Lett. 453:112–114. 2009. View Article : Google Scholar : PubMed/NCBI
8	Tsai SJ, Hong CJ, Liou YJ, et al: Tryptophan hydroxylase 2 gene is associated with major depression and antidepressant treatment response. Prog Neuropsychopharmacol Biol Psychiatry. 33:637–641. 2009. View Article : Google Scholar : PubMed/NCBI
9	Waider J, Araragi N, Gutknecht L and Lesch KP: Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: A perspective. Psychoneuroendocrinology. 36:393–405. 2011. View Article : Google Scholar : PubMed/NCBI
10	Del’Guidice T, Lemay F, Lemasson M, et al: Stimulation of 5 HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation. Neuropsychopharmacology. 39:1125–1134. 2014. View Article : Google Scholar
11	Carkaci Salli N, Salli U, Tekin I, et al: Functional character ization of the S41Y (C2755A) polymorphism of tryptophan hydroxylase 2. J Neurochem. 130:748–758. 2014. View Article : Google Scholar
12	Arango V, Huang YY, Underwood MD and Mann JJ: Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res. 37:375–386. 2003. View Article : Google Scholar : PubMed/NCBI
13	Gutknecht L, Jacob C, Strobel A, et al: Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol. 10:309–320. 2007. View Article : Google Scholar
14	Lim JE, Pinsonneault J, Sadee W and Saffen D: Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry. 12:491–501. 2007.PubMed/NCBI
15	Chen GL, Vallender EJ and Miller GM: Functional characterization of the human TPH2 5′ regulatory region: Untranslated region and polymorphisms modulate gene expression in vitro. Hum Genet. 122:645–657. 2008. View Article : Google Scholar
16	Chen GL and Miller GM: Rhesus monkey tryptophan hydroxylase-2 coding region haplotypes affect mRNA stability. Neuroscience. 155:485–491. 2008. View Article : Google Scholar : PubMed/NCBI
17	Roche S and McKeon P: Support for tryptophan hydroxylase 2 as a susceptibility gene for bipolar affective disorder. Psychiatr Genet. 19:142–146. 2009. View Article : Google Scholar : PubMed/NCBI
18	Zhang C, Li Z, Shao Y, et al: Association study of tryptophan hydroxylase-2 gene in schizophrenia and its clinical features in Chinese Han population. J Mol Neurosci. 43:406–411. 2011. View Article : Google Scholar
19	Zhang Y, Zhang C, Yuan G, et al: Effect of tryptophan hydroxylase-2 rs7305115SNP on suicide attempts risk in major depression. Behav Brain Funct. 6:492010. View Article : Google Scholar
20	Perroud N, Neidhart E, Petit B, et al: Simultaneous analysis of serotonin transporter, tryptophan hydroxylase 1 and 2 gene expression in the ventral prefrontal cortex of suicide victims. Am J Med Genet B Neuropsychiatr Genet. 153B:909–918. 2010.PubMed/NCBI
21	De Luca V, Likhodi O, Van Tol HH, Kennedy JL and Wong AH: Gene expression of tryptophan hydroxylase 2 in post-mortem brain of suicide subjects. Int J Neuropsychopharmacol. 9:21–25. 2006. View Article : Google Scholar
22	Domschke K, Tidow N, Schwarte K, et al: Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response. Int J Neuropsychopharmacol. 17:1167–1176. 2014. View Article : Google Scholar : PubMed/NCBI
23	Dalton VS, Kolshus E and McLoughlin DM: Epigenetics and depression: Return of the repressed. J Affect Disord. 155:1–12. 2014. View Article : Google Scholar
24	Klengel T, Pape J, Binder EB and Mehta D: The role of DNA methylation in stress-related psychiatric disorders. Neuropharmacology. 80:115–132. 2014. View Article : Google Scholar : PubMed/NCBI
25	Williams JB: A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 45:742–747. 1988. View Article : Google Scholar : PubMed/NCBI
26	Leung CM, Wing YK, Kwong PK, Lo A and Shum K: Validation of the Chinese-Cantonese version of the hospital anxiety and depression scale and comparison with the Hamilton Rating Scale of Depression. Acta Psychiatr Scand. 100:456–461. 1999. View Article : Google Scholar
27	Baca-Garcia E, Perez Rodriguez MM, Basurte-Villamor I, et al: Diagnostic stability of psychiatric disorders in clinical practice. Br J Psychiatry. 190:210–216. 2007. View Article : Google Scholar : PubMed/NCBI
28	Spitzer RL and Wakefield JC: DSM-IV diagnostic criterion for clinical significance: Does it help solve the false positives problem? Am J Psychiatry. 156:1856–1864. 1999.PubMed/NCBI
29	Hamilton M: The assessment of anxiety states by rating. Br J Med Psychol. 32:50–55. 1959. View Article : Google Scholar : PubMed/NCBI
30	Ling Y, Zhang C, Xu Y, et al: Promoter methylation-associated silencing of p27kip1 gene with metastasis in esophageal squamous cell carcinoma. Mol Med Rep. 9:1075–1079. 2014.PubMed/NCBI
31	Li LC and Dahiya R: MethPrimer: Designing primers for methylation PCRs. Bioinformatics. 18:1427–1431. 2002. View Article : Google Scholar : PubMed/NCBI
32	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
33	Aberg KA, McClay JL, Nerella S, et al: Methylome-wide association study of schizophrenia: identifying blood biomarker signatures of environmental insults. JAMA Psychiatry. 71:255–264. 2014. View Article : Google Scholar : PubMed/NCBI
34	Meneses A and Liy-Salmeron G: Serotonin and emotion, learning and memory. Rev Neurosci. 23:543–553. 2012.PubMed/NCBI
35	Araragi N and Lesch KP: Serotonin (5-HT) in the regulation of depression-related emotionality: Insight from 5-HT transporter and tryptophan hydroxylase-2 knockout mouse models. Curr Drug Targets. 14:549–570. 2013. View Article : Google Scholar : PubMed/NCBI
36	Chen GL and Miller GM: Tryptophan hydroxylase-2: An emerging therapeutic target for stress disorders. Biochem Pharmacol. 85:1227–1233. 2013. View Article : Google Scholar : PubMed/NCBI
37	Popova NK and Kulikov AV: Targeting tryptophan hydroxylase 2 in affective disorder. Expert Opin Ther Targets. 14:1259–1271. 2010. View Article : Google Scholar : PubMed/NCBI
38	Gardner KL, Hale MW, Oldfield S, Lightman SL, Plotsky PM and Lowry CA: Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus. Neuroscience. 163:991–1001. 2009. View Article : Google Scholar : PubMed/NCBI
39	Mahgoub M and Monteggia LM: Epigenetics and psychiatry. Neurotherapeutics. 10:734–741. 2013. View Article : Google Scholar : PubMed/NCBI
40	Gentile MT, Nawa Y, Lunardi G, Florio T, Matsui H and Colucci-D’Amato L: Tryptophan hydroxylase 2 (TPH2) in a neuronal cell line: Modulation by cell differentiation and NRSF/rest activity. J Neurochem. 123:963–970. 2012. View Article : Google Scholar : PubMed/NCBI
41	Patel PD, Bochar DA, Turner DL, Meng F, Mueller HM and Pontrello CG: Regulation of tryptophan hydroxylase-2 gene expression by a bipartite RE-1 silencer of transcription/neuron restrictive silencing factor (REST/NRSF) binding motif. J Biol Chem. 282:26717–26724. 2007. View Article : Google Scholar : PubMed/NCBI