TY  - JOUR
A1  - Schraut, K. G.
A1  - Jakob, S. B.
A1  - Weidner, M. T.
A1  - Schmitt, A. G.
A1  - Scholz, C. J.
A1  - Strekalova, T.
A1  - El Hajj, N.
A1  - Eijssen, L. M. T.
A1  - Domschke, K.
A1  - Reif, A.
A1  - Haaf, T.
A1  - Ortega, G.
A1  - Steinbusch, H. W. M.
A1  - Lesch, K. P.
A1  - Van den Hove, D. L.
T1  - Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice
JF  - Translational Psychiatry
N2  - The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.
KW  - mice
KW  - DNA
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119199
VL  - 4
ER  - 
TY  - JOUR
A1  - Ziegler, C.
A1  - Richter, J.
A1  - Mahr, M.
A1  - Gajewska, A.
A1  - Schiele, M.A.
A1  - Gehrmann, A.
A1  - Schmidt, B.
A1  - Lesch, K.-P.
A1  - Lang, T.
A1  - Helbig-Lang, S.
A1  - Pauli, P.
A1  - Kircher, T.
A1  - Reif, A.
A1  - Rief, W.
A1  - Vossbeck-Elsebusch, A.N.
A1  - Arolt, V.
A1  - Wittchen, H.-U.
A1  - Hamm, A.O.
A1  - Deckert, J.
A1  - Domschke, K.
T1  - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy
JF  - Translational Psychiatry
N2  - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.
KW  - Adult
KW  - Case-Control Studies
KW  - Cognitive Therapy
KW  - DNA Methylation
KW  - Epigenesis
KW  - Genetic
KW  - Female
KW  - Humans
KW  - Monoamine Oxidase/genetics
KW  - Panic Disorder/genetics
KW  - Panic Disorder/therapy
KW  - Sequence Analysis
KW  - DNA
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422
IS  - 6
ER  -