title: Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain.
abstract: The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.
authors: Radboud University Nijmegen Medical Centre.
authors: Rick H A
authors: RH
authors: van der Doelen
authors: Radboud University Nijmegen Medical Centre.
authors: Ilse A
authors: IA
authors: Arnoldussen
authors: Radboud University Nijmegen Medical Centre.
authors: Hussein
authors: H
authors: Ghareh
authors: Radboud University Nijmegen Medical Centre.
authors: Liselot
authors: L
authors: van Och
authors: Radboud University Nijmegen Medical Centre.
authors: Judith R
authors: JR
authors: Homberg
authors: Radboud University Nijmegen Medical Centre.
authors: Tamás
authors: T
authors: Kozicz
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D008297:Male; D008426:Maternal Deprivation; D010286:Paraventricular Hypothalamic Nucleus; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D013315:Stress, Psychological / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D003346:Corticotropin-Releasing Hormone