Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects

被引：265

作者：

Keller, Simona

Sarchiapone, Marco

Zarrilli, Federica

Videtic, Alja

Ferraro, Angelo

Carli, Vladimir

Sacchetti, Silvana

Lembo, Francesca

Angiolillo, Antonella

Jovanovic, Nikolina

Pisanti, Francesco

Tomaiuolo, Rossella

Monticelli, Antonella

Balazic, Joze

Roy, Alec

Marusic, Andrej

Cocozza, Sergio

Fusco, Alfredo

Bruni, Carmelo B.

Castaldo, Giuseppe

Chiariotti, Lorenzo

机构：

[1] Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples

[2] Dipartimento di Biochimica e Biotecnologie Mediche, Naples

[3] Dipartimento di Chimica Farmaceutica e Tossicologica, Facoltà di Farmacia, Naples

[4] Università degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate, Naples

[5] NOGEC (Naples Oncogenomic Centre), European School of Molecular Medicine (SEMM), Naples

[6] Patologia Clinica ASL Napoli 3, Naples

[7] Dipartimento di Scienze Per la Salute, Università del Molise, Campobasso

[8] Fondazione Leonardo Per le Scienze Mediche, Montegrotto, Padova

[9] Facoltà di Scienze MFN, Università del Molise, Isernia

[10] University of Ljubljana, Ljubljana

[11] Health Research Department, PINT, University of Primorska, Koper

[12] National Prevention of Suicide and Mental Ill-Health (NASP), Karolinska Institutet, Stockholm

[13] Department of Psychiatry, School of Medicine, University of Zagreb, Zagreb

[14] Department of Veteran Affairs East Orange, East Orange, NJ

来源：

ARCHIVES OF GENERAL PSYCHIATRY | 2010年 / 67卷 / 03期

关键词：

D O I：

10.1001/archgenpsychiatry.2010.9

中图分类号：

R749 [精神病学];

学科分类号：

100205 ;

摘要：

Context: Brain-derived neurotrophic factor (BDNF) plays pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. Objectives: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. Design: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. Setting: Academic medical center. Patients or Other Participants: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. Main Outcome Measures: The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. Results: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter exon IV compared with nonsuicide control subjects (P.001). Most of the CpG sites lying in the -300 500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. Conclusions: BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.

引用

页码：258 / 267

页数：10

共 41 条

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