Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects
CONTEXT Brain-derived neurotrophic factor (BDNF) plays a 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 t...
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| creator | Keller, Simona Sarchiapone, Marco Zarrilli, Federica Videtič, 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 |
| description | CONTEXT Brain-derived neurotrophic factor (BDNF) plays a 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 |
| doi_str_mv | 10.1001/archgenpsychiatry.2010.9 |
| format | Article |
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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.Arch Gen Psychiatry. 2010;67(3):258-267--></description><identifier>ISSN: 0003-990X</identifier><identifier>ISSN: 1538-3636</identifier><identifier>EISSN: 1538-3636</identifier><identifier>DOI: 10.1001/archgenpsychiatry.2010.9</identifier><identifier>PMID: 20194826</identifier><identifier>CODEN: ARGPAQ</identifier><language>eng</language><publisher>Chicago, IL: American Medical Association</publisher><subject>Adolescent ; Adult ; Adult and adolescent clinical studies ; Aged ; Biological and medical sciences ; Brain-Derived Neurotrophic Factor - genetics ; Brain-Derived Neurotrophic Factor - metabolism ; Cloning, Molecular - methods ; DNA Methylation - genetics ; Down-Regulation - genetics ; European Continental Ancestry Group - genetics ; Female ; Gene Expression Profiling ; Humans ; Male ; Medical sciences ; Medicin och hälsovetenskap ; Middle Aged ; Polymorphism, Single Nucleotide - genetics ; Promoter Regions, Genetic - genetics ; Promoter Regions, Genetic - physiology ; Psychology. Psychoanalysis. Psychiatry ; Psychopathology. Psychiatry ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Suicide ; Suicide - psychology ; Suicide - statistics & numerical data ; Temporal Lobe - metabolism</subject><ispartof>Archives of general psychiatry, 2010-03, Vol.67 (3), p.258-267</ispartof><rights>2015 INIST-CNRS</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a516t-248f989814e7cf0f3bb3210ee3612f131708d8286b025ecaae7a1ed5d10e28f53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://jamanetwork.com/journals/jamapsychiatry/articlepdf/10.1001/archgenpsychiatry.2010.9$$EPDF$$P50$$Gama$$H</linktopdf><linktohtml>$$Uhttps://jamanetwork.com/journals/jamapsychiatry/fullarticle/10.1001/archgenpsychiatry.2010.9$$EHTML$$P50$$Gama$$H</linktohtml><link.rule.ids>64,230,314,780,784,885,3340,27924,27925,76489,76492</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22561498$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20194826$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:120075486$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Keller, Simona</creatorcontrib><creatorcontrib>Sarchiapone, Marco</creatorcontrib><creatorcontrib>Zarrilli, Federica</creatorcontrib><creatorcontrib>Videtič, Alja</creatorcontrib><creatorcontrib>Ferraro, Angelo</creatorcontrib><creatorcontrib>Carli, Vladimir</creatorcontrib><creatorcontrib>Sacchetti, Silvana</creatorcontrib><creatorcontrib>Lembo, Francesca</creatorcontrib><creatorcontrib>Angiolillo, Antonella</creatorcontrib><creatorcontrib>Jovanovic, Nikolina</creatorcontrib><creatorcontrib>Pisanti, Francesco</creatorcontrib><creatorcontrib>Tomaiuolo, Rossella</creatorcontrib><creatorcontrib>Monticelli, Antonella</creatorcontrib><creatorcontrib>Balazic, Joze</creatorcontrib><creatorcontrib>Roy, Alec</creatorcontrib><creatorcontrib>Marusic, Andrej</creatorcontrib><creatorcontrib>Cocozza, Sergio</creatorcontrib><creatorcontrib>Fusco, Alfredo</creatorcontrib><creatorcontrib>Bruni, Carmelo B</creatorcontrib><creatorcontrib>Castaldo, Giuseppe</creatorcontrib><creatorcontrib>Chiariotti, Lorenzo</creatorcontrib><title>Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects</title><title>Archives of general psychiatry</title><addtitle>Arch Gen Psychiatry</addtitle><description>CONTEXT Brain-derived neurotrophic factor (BDNF) plays a 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.Arch Gen Psychiatry. 2010;67(3):258-267--></description><subject>Adolescent</subject><subject>Adult</subject><subject>Adult and adolescent clinical studies</subject><subject>Aged</subject><subject>Biological and medical sciences</subject><subject>Brain-Derived Neurotrophic Factor - genetics</subject><subject>Brain-Derived Neurotrophic Factor - metabolism</subject><subject>Cloning, Molecular - methods</subject><subject>DNA Methylation - genetics</subject><subject>Down-Regulation - genetics</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Middle Aged</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Promoter Regions, Genetic - physiology</subject><subject>Psychology. Psychoanalysis. Psychiatry</subject><subject>Psychopathology. Psychiatry</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Suicide</subject><subject>Suicide - psychology</subject><subject>Suicide - statistics & numerical data</subject><subject>Temporal Lobe - metabolism</subject><issn>0003-990X</issn><issn>1538-3636</issn><issn>1538-3636</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kT1vFDEQhi0EIkfgB9AgN4hqw9hee-0yBAKRjg8JEHSW1zvmnOzHYe8K3b_H0V1yBaIae-Z5ZoqXEMrgjAGw1y75zS8ct3nnN9HNaXfGoczMA7JiUuhKKKEekhUAiMoY-HlCnuR8Xb4gFX9MTgptas3ViqyvRp_QZezom7efLumXNA3TjIl-xHmz690cp5HGkc4bpD8wjdHfID0vBp0C_bpEHzsstb1GP-en5FFwfcZnh3pKvl---3bxoVp_fn91cb6unGRqrnitg9FGsxobHyCIthWcAaJQjAcmWAO601yrFrhE7xw2jmEnu8JwHaQ4JdV-b_6D26W12xQHl3Z2ctEeWjflhVZKrhtRePNffpum7ijdiYwDNLLWqriv9m4Bfy-YZzvE7LHv3YjTkm1Zr4xkNRRS70mfppwThvs7DOxtbPaf2OxtbNYU9cXhyNIO2N2LdzkV4OUBcNm7PiQ3-piPHJeK1UYX7vmec4M7ThkoLsRf6umvIQ</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Keller, Simona</creator><creator>Sarchiapone, Marco</creator><creator>Zarrilli, Federica</creator><creator>Videtič, Alja</creator><creator>Ferraro, Angelo</creator><creator>Carli, Vladimir</creator><creator>Sacchetti, Silvana</creator><creator>Lembo, Francesca</creator><creator>Angiolillo, Antonella</creator><creator>Jovanovic, Nikolina</creator><creator>Pisanti, Francesco</creator><creator>Tomaiuolo, Rossella</creator><creator>Monticelli, Antonella</creator><creator>Balazic, Joze</creator><creator>Roy, Alec</creator><creator>Marusic, Andrej</creator><creator>Cocozza, Sergio</creator><creator>Fusco, Alfredo</creator><creator>Bruni, Carmelo B</creator><creator>Castaldo, Giuseppe</creator><creator>Chiariotti, Lorenzo</creator><general>American Medical Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20100301</creationdate><title>Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects</title><author>Keller, Simona ; Sarchiapone, Marco ; Zarrilli, Federica ; Videtič, 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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a516t-248f989814e7cf0f3bb3210ee3612f131708d8286b025ecaae7a1ed5d10e28f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Adult and adolescent clinical studies</topic><topic>Aged</topic><topic>Biological and medical sciences</topic><topic>Brain-Derived Neurotrophic Factor - genetics</topic><topic>Brain-Derived Neurotrophic Factor - metabolism</topic><topic>Cloning, Molecular - methods</topic><topic>DNA Methylation - genetics</topic><topic>Down-Regulation - genetics</topic><topic>European Continental Ancestry Group - genetics</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Middle Aged</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Promoter Regions, Genetic - physiology</topic><topic>Psychology. Psychoanalysis. Psychiatry</topic><topic>Psychopathology. Psychiatry</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Suicide</topic><topic>Suicide - psychology</topic><topic>Suicide - statistics & numerical data</topic><topic>Temporal Lobe - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Keller, Simona</creatorcontrib><creatorcontrib>Sarchiapone, Marco</creatorcontrib><creatorcontrib>Zarrilli, Federica</creatorcontrib><creatorcontrib>Videtič, Alja</creatorcontrib><creatorcontrib>Ferraro, Angelo</creatorcontrib><creatorcontrib>Carli, Vladimir</creatorcontrib><creatorcontrib>Sacchetti, Silvana</creatorcontrib><creatorcontrib>Lembo, Francesca</creatorcontrib><creatorcontrib>Angiolillo, Antonella</creatorcontrib><creatorcontrib>Jovanovic, Nikolina</creatorcontrib><creatorcontrib>Pisanti, Francesco</creatorcontrib><creatorcontrib>Tomaiuolo, Rossella</creatorcontrib><creatorcontrib>Monticelli, Antonella</creatorcontrib><creatorcontrib>Balazic, Joze</creatorcontrib><creatorcontrib>Roy, Alec</creatorcontrib><creatorcontrib>Marusic, Andrej</creatorcontrib><creatorcontrib>Cocozza, Sergio</creatorcontrib><creatorcontrib>Fusco, Alfredo</creatorcontrib><creatorcontrib>Bruni, Carmelo B</creatorcontrib><creatorcontrib>Castaldo, Giuseppe</creatorcontrib><creatorcontrib>Chiariotti, Lorenzo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Archives of general psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Keller, Simona</au><au>Sarchiapone, Marco</au><au>Zarrilli, Federica</au><au>Videtič, Alja</au><au>Ferraro, Angelo</au><au>Carli, Vladimir</au><au>Sacchetti, Silvana</au><au>Lembo, Francesca</au><au>Angiolillo, Antonella</au><au>Jovanovic, Nikolina</au><au>Pisanti, Francesco</au><au>Tomaiuolo, Rossella</au><au>Monticelli, Antonella</au><au>Balazic, Joze</au><au>Roy, Alec</au><au>Marusic, Andrej</au><au>Cocozza, Sergio</au><au>Fusco, Alfredo</au><au>Bruni, Carmelo B</au><au>Castaldo, Giuseppe</au><au>Chiariotti, Lorenzo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects</atitle><jtitle>Archives of general psychiatry</jtitle><addtitle>Arch Gen Psychiatry</addtitle><date>2010-03-01</date><risdate>2010</risdate><volume>67</volume><issue>3</issue><spage>258</spage><epage>267</epage><pages>258-267</pages><issn>0003-990X</issn><issn>1538-3636</issn><eissn>1538-3636</eissn><coden>ARGPAQ</coden><abstract>CONTEXT Brain-derived neurotrophic factor (BDNF) plays a 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.Arch Gen Psychiatry. 2010;67(3):258-267--></abstract><cop>Chicago, IL</cop><pub>American Medical Association</pub><pmid>20194826</pmid><doi>10.1001/archgenpsychiatry.2010.9</doi><tpages>10</tpages></addata></record> |
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| ispartof | Archives of general psychiatry, 2010-03, Vol.67 (3), p.258-267 |
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| subjects | Adolescent Adult Adult and adolescent clinical studies Aged Biological and medical sciences Brain-Derived Neurotrophic Factor - genetics Brain-Derived Neurotrophic Factor - metabolism Cloning, Molecular - methods DNA Methylation - genetics Down-Regulation - genetics European Continental Ancestry Group - genetics Female Gene Expression Profiling Humans Male Medical sciences Medicin och hälsovetenskap Middle Aged Polymorphism, Single Nucleotide - genetics Promoter Regions, Genetic - genetics Promoter Regions, Genetic - physiology Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Messenger - metabolism Suicide Suicide - psychology Suicide - statistics & numerical data Temporal Lobe - metabolism |
| title | Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects |
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