期刊
NATURE NEUROSCIENCE
卷 16, 期 1, 页码 33-41出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3275
关键词
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资金
- European Research Council [281338]
- National Alliance for Research in Schizophrenia and Affective Disorders
- Behrens Weise Stiftung
- National Institute of Mental Health [MH071538, MH58922]
- National Institute for Health Research Biomedical Research Centre for Mental Health
- Institute of Psychiatry
- South London and Maudsley National Health System Foundation Trust
- UK Medical Research Council [G108/603]
- Commission of European Communities 7th Framework Programme Collaborative Project [22963]
- Public Health Service from the Clinical and Translational Science Award program [UL1 RR025008]
- US National Institutes of Health
- National Center for Research Resources
- K Award [K01 MH073698-01]
- Medical Research Council [G108/603] Funding Source: researchfish
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000454] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR025008] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [K01MH073698, P50MH058922] Funding Source: NIH RePORTER
- MRC [G108/603] Funding Source: UKRI
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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