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| Status |
Public on Mar 01, 2019 |
| Title |
Glucocorticoid Exposure During Hippocampal Neurogenesis Primes Future Stress Response by Inducing Long-Lasting Changes in DNA Methylation [methylation] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
Prenatal stress exposure is associated with the risk for psychiatric disorders later in life. This may be mediated via enhanced exposure to glucocorticoids (GCs), known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor cell (HPC) line, we assessed the short- and long-term effects of GC exposure during neurogenesis on mRNA expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG sites and in the expression of 3,857 transcripts at FDR ≤ 0.1 and an absolsute change in expression of 1.15. HPC gene expression and GC-affected DNAm profiles were enriched for changes observed during human fetal brain development. Differentially methylated sites (DMSs) with GC exposure clustered into four trajectories over HPC-differentiation, with transient as well as long-lasting DNAm changes. Lasting DMSs mapped to distinct functional pathways and were selectively enriched for poised and bivalent enhancer marks. Lasting DMSs had little correlation with lasting gene expression changes, but were associated with a significantly enhanced transcriptional response to a second acute GC challenge. A significant subset of lasting DMSs was also responsive to an acute GC-challenge in peripheral blood. These tissue-overlapping DMSs were used to compute a poly-epigenetic score that predicted exposure to conditions of excessive prenatal GC in newborn cord blood. Overall, our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes. Such altered set points may relate to differential vulnerability to stress exposure later in life.
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| Overall design |
The immortalized, multipotent human fetal HPC line HPC03A/07 provided by ReNeuron Ltd, UK was used. HPC03A/07 cells proliferated in the presence of growth factors (EGF, FGF) and 4-hydroxytamoxifen (4-OHT), while differentiation is initiated upon growth factor and 4-OHT removal. Cells were first treated with either 1 μM of dexamethasone (dex) or vehicle (ETOH) in four different experiments with independent replicates. Cells were treated during 3 days of proliferation (Pro, veh n=6, dex n=6) or during both proliferation and 7 days of differentiation induced by the removal of growth factors and 4-OHT (Pro-diff, veh n=7, dex n=7). Next, treatments were applied during both proliferation (3 days) and differentiation (7 days) and cells were cultured for an additional 20 days of washout without dex or vehicle (Pro-diff+WO, veh n=8, dex n=8) to assess the lasting effects of the treatment. Lastly, cells were treated after proliferation and differentiation for 10 days followed by 20 days of washout (Post+WO, veh n=9, dex n=9) to compare lasting effects between treatments applied before and after differentiation.
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| Contributor(s) |
Arloth J, Provençal N, Binder EB |
| Citation(s) |
31399550 |
| Submission date |
Sep 12, 2018 |
| Last update date |
Oct 13, 2020 |
| Contact name |
Janine Arloth |
| Organization name |
Max Planck Institute of Psychiatry
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| Street address |
Kraepelinstr. 2-10
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| City |
Munich |
| ZIP/Postal code |
80804 |
| Country |
Germany |
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| Platforms (1) |
| GPL13534 |
Illumina HumanMethylation450 BeadChip (HumanMethylation450_15017482) |
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| Samples (60)
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| This SubSeries is part of SuperSeries: |
| GSE119847 |
Glucocorticoid Exposure During Hippocampal Neurogenesis Primes Future Stress Response by Inducing Long-Lasting Changes in DNA Methylation |
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| Relations |
| BioProject |
PRJNA490451 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE119846_RAW.tar |
677.9 Mb |
(http)(custom) |
TAR (of IDAT) |
| Processed data included within Sample table |
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