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

• Type of Material: Article
• Authors: Nadine Provencal, Max Planck Institute of Psychiatry; Janine Arloth, Max Planck Institute of Psychiatry; Annamaria Cattaneo, Kings’s College London; Christoph Anacker, Columbia University; Nadia Cattane, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli; Tobias Wiechmann, Max Planck Institute of Psychiatry; Simone Roeh, Max Planck Institute of Psychiatry; Maik Koedel, Max Planck Institute of Psychiatry; Torsten Klengel, Harvard University; Darina Czamara, Max Planck Institute of Psychiatry; Nikola S. Mueller, Helmholtz Zentrum Munchen; Jari Lahti, University of Helsinki; Katri Raikkonen, University of Helsinki; Carmine M. Pariante, Kings's College London; Elisabeth Binder, Emory University
• Language: English
• Date: 2020-09-22
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: Published under the PNAS license
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1820842116
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 117
• Issue: 38
• Start Page: 23280
• End Page: 23285
• Grant/Funding Information: This study was funded by Federal Ministry of Education and Research (BMBF) Grant Berlin-longitudinal child study FKZ 01KR1301B (to E.B.B.) and European research council (ERC) Starting Grant GxE molmech 281338 (to E.B.B.) within the 7th framework (FP7) funding scheme of the European Union. N.P. was funded by a research fellowship from the Canadian Institute of Health Research. A.C. was funded by the Italian Ministry of Health (Ricerca Corrente). C.A. was funded by a K99/R00 Pathway to Independence Award from NIH Grant K99 MH108719. T.K. received funding from Brain and Behavior Research Foundation Grant YI 20895 and Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant 1R21HD088931. The PREDO cohort was funded by Academy of Finland Grants 1284859, 12848591, and 1312670 and Signe and Ane Gyllenberg Foundation grants (to K.R., primary investigator of the PREDO team).
• Keywords: glucocorticoids; ANXIETY; IMPACT; RECEPTOR; Science & Technology - Other Topics; BRAIN; ORIGINS; MATERNAL STRESS; EXPRESSION; PRENATAL STRESS; Multidisciplinary Sciences; Science & Technology; BEHAVIOR; DEPRESSION; hippocampal neurogenesis; DNA methylation; gene expression; prenatal stress
• Research Categories: Psychology, Behavioral; Biology, Genetics; Health Sciences, Obstetrics and Gynecology

Abstract

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.