Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression
The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult male...
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| creator | Wang, Dongsha Szyf, Moshe Benkelfat, Chawki Provençal, Nadine Turecki, Gustavo Caramaschi, Doretta Côté, Sylvana M Vitaro, Frank Tremblay, Richard E Booij, Linda |
| description | The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function. |
| doi_str_mv | 10.1371/journal.pone.0039501 |
| format | Article |
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Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0039501</identifier><identifier>PMID: 22745770</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aggression ; Aggression - physiology ; Aggressiveness ; Biology ; Biometrics ; Blood ; Blood cells ; Brain ; Brain - metabolism ; Brain research ; Change detection ; Childhood ; Children ; CpG islands ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - genetics ; Emission analysis ; Emission measurements ; Epigenetic inheritance ; Epigenetics ; Gene expression ; Genes ; Health care ; Human behavior ; Humans ; Juvenile delinquency ; Leukocytes ; Lymphocytes ; Lymphocytes T ; Male ; Males ; Medicine ; Mental depression ; Methylation ; Monocytes ; Nonviolence ; Pharmacology ; Phenols (Class of compounds) ; Positron emission ; Positron emission tomography ; Promoter Regions, Genetic - genetics ; Psychiatry ; Psychobiology ; Psychosis ; Serotonin ; Serotonin - metabolism ; Serotonin Plasma Membrane Transport Proteins - genetics ; Studies ; Synthesis ; T cells ; Thiophenes - metabolism ; Tomography ; Transcription ; Transcription (Genetics)</subject><ispartof>PloS one, 2012-06, Vol.7 (6), p.e39501-e39501</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Wang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c743t-c536e0d562b781a8ce6d66787b209526f2d2d4a921834efacd0debdb6c89a6043</citedby><cites>FETCH-LOGICAL-c743t-c536e0d562b781a8ce6d66787b209526f2d2d4a921834efacd0debdb6c89a6043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379993/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379993/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22745770$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gelovani, Juri G.</contributor><creatorcontrib>Wang, Dongsha</creatorcontrib><creatorcontrib>Szyf, Moshe</creatorcontrib><creatorcontrib>Benkelfat, Chawki</creatorcontrib><creatorcontrib>Provençal, Nadine</creatorcontrib><creatorcontrib>Turecki, Gustavo</creatorcontrib><creatorcontrib>Caramaschi, Doretta</creatorcontrib><creatorcontrib>Côté, Sylvana M</creatorcontrib><creatorcontrib>Vitaro, Frank</creatorcontrib><creatorcontrib>Tremblay, Richard E</creatorcontrib><creatorcontrib>Booij, Linda</creatorcontrib><title>Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.</description><subject>Adult</subject><subject>Aggression</subject><subject>Aggression - physiology</subject><subject>Aggressiveness</subject><subject>Biology</subject><subject>Biometrics</subject><subject>Blood</subject><subject>Blood cells</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Brain research</subject><subject>Change detection</subject><subject>Childhood</subject><subject>Children</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Emission analysis</subject><subject>Emission measurements</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Health care</subject><subject>Human behavior</subject><subject>Humans</subject><subject>Juvenile delinquency</subject><subject>Leukocytes</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Males</subject><subject>Medicine</subject><subject>Mental depression</subject><subject>Methylation</subject><subject>Monocytes</subject><subject>Nonviolence</subject><subject>Pharmacology</subject><subject>Phenols (Class of compounds)</subject><subject>Positron emission</subject><subject>Positron emission tomography</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Psychiatry</subject><subject>Psychobiology</subject><subject>Psychosis</subject><subject>Serotonin</subject><subject>Serotonin - metabolism</subject><subject>Serotonin Plasma Membrane Transport Proteins - genetics</subject><subject>Studies</subject><subject>Synthesis</subject><subject>T cells</subject><subject>Thiophenes - metabolism</subject><subject>Tomography</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk8-O0zAQxiMEYpeFN0BgCQnBocWxHSe5IFXlX6WKRSxwtRx7krhK467tFPoKPDUu7a4atAfkQyz7932TGc8kydMUT1Oap29WdnC97KYb28MUY1pmOL2XnKclJRNOML1_sj9LHnm_wjijBecPkzNCcpblOT5Pfn8BZzYtONmhq-Wczxh693mG1hDaXSeDsT0yHknvrTIygEY_TWiR6dHWbG3EpB8ceGRr1A5r2aPKyXjpwdlg-_1u14cW_N6j10i1ptOttRpt2p03KgaVTRMNfAz0OHlQy87Dk-P3Ivn-4f23-afJ8vLjYj5bTlTOaJiojHLAOuOkyotUFgq45jwv8orgMiO8JppoJkuSFpRBLZXGGipdcVWUkmNGL5LnB99NZ704ltGLlBKelpylJBKLA6GtXImNM2vpdsJKI_4eWNcI6YJRHQiMgfCoK6sas7qSBWEMCEtzSjPJWRW93h6jDdUatII-xFqPTMc3vWlFY7eC0rwsSxoNXh0NnL0ewAexNl5B18ke7BD_GxNSsJhtGdEX_6B3Z3ekGhkTMH1tY1y1NxUzFpsi4znPIzW9g4pLw9qo2HO1iecjweuRIDIBfoVGDt6LxdXX_2cvf4zZlydsC7ILrbfdsO9NPwbZAVTOeu-gvi1yisV-ZG6qIfYjI44jE2XPTh_oVnQzI_QPNfUSNw</recordid><startdate>20120620</startdate><enddate>20120620</enddate><creator>Wang, Dongsha</creator><creator>Szyf, Moshe</creator><creator>Benkelfat, Chawki</creator><creator>Provençal, Nadine</creator><creator>Turecki, Gustavo</creator><creator>Caramaschi, Doretta</creator><creator>Côté, Sylvana M</creator><creator>Vitaro, Frank</creator><creator>Tremblay, Richard E</creator><creator>Booij, Linda</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120620</creationdate><title>Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression</title><author>Wang, Dongsha ; Szyf, Moshe ; Benkelfat, Chawki ; Provençal, Nadine ; Turecki, Gustavo ; Caramaschi, Doretta ; Côté, Sylvana M ; Vitaro, Frank ; Tremblay, Richard E ; Booij, Linda</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c743t-c536e0d562b781a8ce6d66787b209526f2d2d4a921834efacd0debdb6c89a6043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adult</topic><topic>Aggression</topic><topic>Aggression - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Dongsha</au><au>Szyf, Moshe</au><au>Benkelfat, Chawki</au><au>Provençal, Nadine</au><au>Turecki, Gustavo</au><au>Caramaschi, Doretta</au><au>Côté, Sylvana M</au><au>Vitaro, Frank</au><au>Tremblay, Richard E</au><au>Booij, Linda</au><au>Gelovani, Juri G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-20</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e39501</spage><epage>e39501</epage><pages>e39501-e39501</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The main challenge in addressing the role of DNA methylation in human behaviour is the fact that the brain is inaccessible to epigenetic analysis in living humans. Using positron emission tomography (PET) measures of brain serotonin (5-HT) synthesis, we found in a longitudinal sample that adult males with high childhood-limited aggression (C-LHPA) had lower in vivo 5-HT synthesis in the orbitofrontal cortex (OBFC). Here we hypothesized that 5-HT alterations associated with childhood aggression were linked to differential DNA methylation of critical genes in the 5-HT pathway and these changes were also detectable in peripheral white blood cells. Using pyrosequencing, we determined the state of DNA methylation of SLC6A4 promoter in T cells and monocytes isolated from blood of cohort members (N = 25) who underwent a PET scan, and we examined whether methylation status in the blood is associated with in vivo brain 5-HT synthesis. Higher levels of methylation were observed in both T cells and monocytes at specific CpG sites in the C-LHPA group. DNA methylation of SLC6A4 in monocytes appears to be associated more reliably with group membership than T cells. In both cell types the methylation state of these CpGs was associated with lower in vivo measures of brain 5-HT synthesis in the left and right lateral OBFC (N = 20) where lower 5-HT synthesis in C-LHPA group was observed. Furthermore, in vitro methylation of the SLC6A4 promoter in a luciferase reporter construct suppresses its transcriptional activity supporting a functional role of DNA methylation in SLC6A4 promoter regulation. These findings indicate that state of SLC6A4 promoter methylation is altered in peripheral white blood cells of individuals with physical aggression during childhood. This supports the relevance of peripheral DNA methylation for brain function and suggests that peripheral SLC6A4 DNA methylation could be a marker of central 5-HT function.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22745770</pmid><doi>10.1371/journal.pone.0039501</doi><tpages>e39501</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-06, Vol.7 (6), p.e39501-e39501 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326196412 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Aggression Aggression - physiology Aggressiveness Biology Biometrics Blood Blood cells Brain Brain - metabolism Brain research Change detection Childhood Children CpG islands Deoxyribonucleic acid DNA DNA methylation DNA Methylation - genetics Emission analysis Emission measurements Epigenetic inheritance Epigenetics Gene expression Genes Health care Human behavior Humans Juvenile delinquency Leukocytes Lymphocytes Lymphocytes T Male Males Medicine Mental depression Methylation Monocytes Nonviolence Pharmacology Phenols (Class of compounds) Positron emission Positron emission tomography Promoter Regions, Genetic - genetics Psychiatry Psychobiology Psychosis Serotonin Serotonin - metabolism Serotonin Plasma Membrane Transport Proteins - genetics Studies Synthesis T cells Thiophenes - metabolism Tomography Transcription Transcription (Genetics) |
| title | Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression |
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