Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.
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DOI：
10.1038/nn.3275
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发表时间：
2013-01
影响因子：
25
通讯作者：
Binder, Elisabeth B.
中科院分区：
文献类型：
--
作者：
Klengel, Torsten;Mehta, Divya;Anacker, Christoph;Rex-Haffner, Monika;Pruessner, Jens C.;Pariante, Carmine M.;Pace, Thaddeus W. W.;Mercer, Kristina B.;Mayberg, Helen S.;Bradley, Bekh;Nemeroff, Charles B.;Holsboer, Florian;Heim, Christine M.;Ressler, Kerry J.;Rein, Theo;Binder, Elisabeth B.
虽然遗传易感性和环境暴露相互作用影响人脑的发育和功能，最终导致精神障碍的风险已经引起了广泛的兴趣，但相应的分子机制尚未被阐明。我们发现，改变FK506结合蛋白5(FKBP5)基因转录起始点和长程增强子之间染色质相互作用的功能性多态，通过FKBP5功能性糖皮质激素反应元件中等位基因特异性的、童年创伤相关的DNA去甲基化，增加了成年后发生应激相关精神疾病的风险。FKBP5是应激激素系统的重要调节因子。这种去甲基化与应激依赖基因转录增加有关，随后是应激激素系统的长期失调，并对免疫细胞和与应激调节相关的大脑区域的功能产生整体影响。这种对基因导向的长期环境反应性分子机制的识别将有助于设计更有效的应激相关疾病的治疗策略。
Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.
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影响因子：
1.3
作者：
COLLINS, DL;NEELIN, P;EVANS, AC
通讯作者：
EVANS, AC
影响因子：
11
作者：
Anacker, C.;Zunszain, P. A.;Cattaneo, A.;Carvalho, L. A.;Garabedian, M. J.;Thuret, S.;Price, J.;Pariante, C. M.
通讯作者：
Pariante, C. M.
影响因子：
120.7
作者：
Binder, Elisabeth B.;Bradley, Rebekah G.;Ressler, Kerry J.
通讯作者：
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影响因子：
3.7
作者：
Binder, E. B.;Kuenzel, H. E.;Holsboer, F.
通讯作者：
Holsboer, F.
影响因子：
30.8
作者：
Binder, EB;Salyakina, D;Muller-Myhsok, B
通讯作者：
Muller-Myhsok, B