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

Nadine Provençal, Janine Arloth, Annamaria Cattaneo, Christoph Anacker, Nadia Cattane, Tobias Wiechmann, Simone Röh, Maik Ködel, Torsten Klengel, Darina Czamara, Nikola S Müller, Jari Lahti, Katri Räikkönen, Carmine M Pariante, Elisabeth B Binder, PREDO team, Eero Kajantie, Esa Hämäläinen, Pia Villa, Hannele Laivuori

Research output: Contribution to journalArticleScientificpeer-review

33 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)23280-23285
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
Publication statusPublished - 22 Sept 2020
Publication typeA1 Journal article-refereed


  • Cohort Studies
  • DNA Methylation/drug effects
  • Female
  • Gene Expression Regulation
  • Glucocorticoids/adverse effects
  • Hippocampus/drug effects
  • Humans
  • Male
  • Neurogenesis/drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects/etiology
  • Stress, Physiological/drug effects

Publication forum classification

  • Publication forum level 3


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