@article{deNijsChoeSteinbuschetal.2019, author = {de Nijs, Laurence and Choe, Kyonghwan and Steinbusch, Hellen and Schijns, Olaf E. M. G. and Dings, Jim and van den Hove, Daniel L. A. and Rutten, Bart P. F. and Hoogland, Govert}, title = {DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0721-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223636}, year = {2019}, abstract = {Background Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is a common pharmaco-resistant epilepsy referred for adult epilepsy surgery. Though associated with prolonged febrile seizures (FS) in childhood, the neurobiological basis for this relationship is not fully understood and currently no preventive or curative therapies are available. DNA methylation, an epigenetic mechanism catalyzed by DNA methyltransferases (DNMTs), potentially plays a pivotal role in epileptogenesis associated with FS. In an attempt to start exploring this notion, the present cross-sectional pilot study investigated whether global DNA methylation levels (5-mC and 5-hmC markers) and DNMT isoforms (DNMT1, DNMT3a1, and DNMT3a2) expression would be different in hippocampal and neocortical tissues between controls and TLE patients with or without a history of FS. Results We found that global DNA methylation levels and DNMT3a2 isoform expression were lower in the hippocampus for all TLE groups when compared to control patients, with a more significant decrease amongst the TLE groups with a history of FS. Interestingly, we showed that DNMT3a1 expression was severely diminished in the hippocampus of TLE patients with a history of FS in comparison with control and other TLE groups. In the neocortex, we found a higher expression of DNMT1 and DNMT3a1 as well as increased levels of global DNA methylation for all TLE patients compared to controls. Conclusion Together, the findings of this descriptive cross-sectional pilot study demonstrated brain region-specific changes in DNMT1 and DNMT3a isoform expression as well as global DNA methylation levels in human TLE with or without a history of FS. They highlighted a specific implication of DNMT3a isoforms in TLE after FS. Therefore, longitudinal studies that aim at targeting DNMT3a isoforms to evaluate the potential causal relationship between FS and TLE or treatment of FS-induced epileptogenesis seem warranted.}, language = {en} } @article{FiedlerHirschElHajjetal.2019, author = {Fiedler, David and Hirsch, Daniela and El Hajj, Nady and Yang, Howard H. and Hu, Yue and Sticht, Carsten and Nanda, Indrajit and Belle, Sebastian and Rueschoff, Josef and Lee, Maxwell P. and Ried, Thomas and Haaf, Thomas and Gaiser, Timo}, title = {Genome-wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine-phosphate-guanine methylation and histological subtypes}, series = {Genes, Chromosomes and Cancer}, volume = {58}, journal = {Genes, Chromosomes and Cancer}, number = {11}, doi = {10.1002/gcc.22787}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212676}, pages = {783 -- 797}, year = {2019}, abstract = {Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin-fixed paraffin-embedded colorectal low-grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10\%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98\% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99\% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46\% hypermethylated). DMPs in cytosine-phosphate-guanine (CpG) islands were frequently hypermethylated, whereas open sea- and shelf-regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.}, language = {en} } @article{WeidnerLardenoijeEijssenetal.2019, author = {Weidner, Magdalena T. and Lardenoije, Roy and Eijssen, Lars and Mogavero, Floriana and De Groodt, Lilian P. M. T. and Popp, Sandy and Palme, Rupert and F{\"o}rstner, Konrad U. and Strekalova, Tatyana and Steinbusch, Harry W. M. and Schmitt-B{\"o}hrer, Angelika G. and Glennon, Jeffrey C. and Waider, Jonas and van den Hove, Daniel L. A. and Lesch, Klaus-Peter}, title = {Identification of cholecystokinin by genome-wide profiling as potential mediator of serotonin-dependent behavioral effects of maternal separation in the amygdala}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2019.00460}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201340}, pages = {460}, year = {2019}, abstract = {Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.}, language = {en} } @article{WiechmannRoehSaueretal.2019, author = {Wiechmann, Tobias and R{\"o}h, Simone and Sauer, Susann and Czamara, Darina and Arloth, Janine and K{\"o}del, Maik and Beintner, Madita and Knop, Lisanne and Menke, Andreas and Binder, Elisabeth B. and Proven{\c{c}}al, Nadine}, title = {Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0682-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233673}, year = {2019}, abstract = {Background Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. Results We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. Conclusion Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.}, language = {en} }