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Provençal, N.* ; Arloth, J. ; Cattaneo, A.* ; Anacker, C.* ; Cattane, N.* ; Wiechmann, T.* ; Röh, S.* ; Ködel, M.* ; Klengel, T.* ; Czamara, D.* ; Müller, N.S.* ; Lahti, J.* ; Räikkönen, K.* ; Pariante, C.M.* ; Binder, E.B.*

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

Proc. Natl. Acad. Sci. U.S.A. 117, 23280-23285 (2019)
Verlagsversion Postprint DOI
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dna Methylation ; Glucocorticoids ; Hippocampal Neurogenesis ; Gene Expression ; Prenatal Stress; Prenatal Stress; Maternal Stress; Brain; Expression; Anxiety; Impact; Depression; Behavior; Receptor; Origins
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Quellenangaben Band: 117, Heft: 38, Seiten: 23280-23285 Artikelnummer: , Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Begutachtungsstatus
Förderungen Signe and Ane Gyllenberg Foundation
European research council (ERC) Starting Grant GxE molmech within the 7th framework (FP7) funding scheme of the European Union
Canadian Institute of Health Research
Italian Ministry of Health
NIH
Brain and Behavior Research Foundation
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Academy of Finland
Academy of Finland
Academy of Finland
Federal Ministry of Education and Research (BMBF)