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Proc Natl Acad Sci U S A. 2019 Aug 9. pii: 201820842. doi: 10.1073/pnas.1820842116. [Epub ahead of print]

Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation.

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Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Healthy Starts Theme British Columbia Children's Hospital Research Institute, Vancouver, BC V5M 3E8, Canada.
Institute of Computational Biology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Biological Psychiatric Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy.
Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, Kings's College London, London WC2R 2LS, United Kingdom.
Department of Psychiatry, Division of Systems Neuroscience, Columbia University and Research Foundation for Mental Hygiene, New York State Psychiatric Institute, New York, NY 10032.
Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478.
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, 37075 Göttingen, Germany.
Department of Psychology and Logopedics, University of Helsinki, Helsinki 00014, Finland.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany;
Department of Psychiatry and Behavioral Sciences, Emory University Medical School, Atlanta, GA 30322.


Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are 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 messenger RNA (mRNA) expression and DNA methylation (DNAm) profiles. GC exposure induced changes in DNAm at 27,812 CpG dinucleotides and in the expression of 3,857 transcripts (false discovery rate [FDR] ≤ 0.1 and absolute fold change [FC] expression ≥ 1.15). HPC 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 4 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 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 polyepigenetic score that predicted exposure to conditions associated with altered prenatal GCs in newborn's cord blood DNA. 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.


DNA methylation; gene expression; glucocorticoids; hippocampal neurogenesis; prenatal stress


Conflict of interest statement

The authors declare no conflict of interest.

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