Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.
Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression.
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DOI：
10.1371/journal.pone.0039501
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Booij L
中科院分区：
文献类型：
--
作者：
Wang D;Szyf M;Benkelfat C;Provençal N;Turecki G;Caramaschi D;Côté SM;Vitaro F;Tremblay RE;Booij L
解决DNA甲基化在人类行为中的作用的主要挑战是大脑无法进行活体表观遗传分析。使用正电子发射断层扫描（PET）测量大脑5-羟色胺（5-HT）的合成，我们发现在纵向样本中，成年男性与高儿童期有限的侵略（C-LHPA）有较低的体内5-HT合成眶额皮质（OBFC）。在这里，我们假设与儿童期攻击性相关的5-HT改变与5-HT通路中关键基因的差异DNA甲基化有关，并且这些变化在外周白色血细胞中也可检测到。使用焦磷酸测序，我们确定了从接受PET扫描的队列成员（N = 25）的血液中分离的T细胞和单核细胞中SLC6A4启动子的DNA甲基化状态，并且我们检查了血液中的甲基化状态是否与体内脑5-HT合成相关。 在C-LHPA组中，在T细胞和单核细胞中的特定CpG位点处观察到较高水平的甲基化。单核细胞中SLC6A4的DNA甲基化似乎比T细胞更可靠地与组成员关系相关。在两种细胞类型中，这些CpG的甲基化状态与左侧和右侧OBFC（N = 20）中较低的脑5-HT合成的体内测量相关，其中在C-LHPA组中观察到较低的5-HT合成。 此外，在体外甲基化的SLC6A4启动子的荧光素酶报告构建体抑制其转录活性支持的功能作用的DNA甲基化的SLC6A4启动子调控。这些发现表明，在儿童时期具有身体攻击性的个体的外周白色血细胞中，SLC6A4启动子甲基化的状态发生了改变。这支持了外周DNA甲基化与脑功能的相关性，并表明外周SLC6A4 DNA甲基化可能是中枢5-HT功能的标志物。
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.
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影响因子：
3.2
作者：
NUR, I;SZYF, M;RAZIN, S
通讯作者：
RAZIN, S
影响因子：
5.6
作者：
Hernández, E;Lastra, S;Lima, L
通讯作者：
Lima, L
DOI：
10.1002/ajmg.b.30657
发表时间：
2008-07-05
影响因子：
2.8
作者：
Philibert, Robert A.;Sandhu, Harinder;Hollenbeck, Nancy;Gunter, Tracy;Adams, William;Madan, Anup
通讯作者：
Madan, Anup
影响因子：
56.9
作者：
Ansorge, MS;Zhou, MM;Gingrich, JA
通讯作者：
Gingrich, JA
影响因子：
4.3
作者：
Marazziti, D;Dell'Osso, B;Cassano, GB
通讯作者：
Cassano, GB