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

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Prenatal stress exposure is associated with a wide range of health problems later in life. This may be mediated in part via glucocorticoid (GC) exposure during fetal development known to impact neurogenesis and induce epigenetic changes. Using a human fetal hippocampal progenitor cell line to assess the effects of GCs, we observe that exposure to GCs early during neurogenesis results in lasting changes in DNA methylation (DNAm). Lasting DNAm alterations are associated with significantly enhanced transcriptional response to a subsequent GC exposure. Our data suggest that early exposure to GCs changes 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.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
JournalProceedings of the National Academy of Sciences of the United States of America
ISSN0027-8424
DOIs
Publication statusPublished - 9 Aug 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3124 Neurology and psychiatry

Cite this

Provençal, Nadine ; Arloth, Janine ; Cattaneo, Annamaria ; Anacker, Christoph ; Cattane, Nadia ; Wiechmann, Tobias ; Röh, Simone ; Ködel, Maik ; Klengel, Torsten ; Czamara, Darina ; Müller, Nikola S. ; Lahti, Jari ; Räikkönen, Katri ; Pariante, Carmine M. ; Binder, Elisabeth B. / Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation. In: Proceedings of the National Academy of Sciences of the United States of America. 2019.
@article{ee56d460ae75406fa90167b269b2cba6,
title = "Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation",
abstract = "Prenatal stress exposure is associated with a wide range of health problems later in life. This may be mediated in part via glucocorticoid (GC) exposure during fetal development known to impact neurogenesis and induce epigenetic changes. Using a human fetal hippocampal progenitor cell line to assess the effects of GCs, we observe that exposure to GCs early during neurogenesis results in lasting changes in DNA methylation (DNAm). Lasting DNAm alterations are associated with significantly enhanced transcriptional response to a subsequent GC exposure. Our data suggest that early exposure to GCs changes 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.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.",
keywords = "3124 Neurology and psychiatry",
author = "Nadine Proven{\cc}al and Janine Arloth and Annamaria Cattaneo and Christoph Anacker and Nadia Cattane and Tobias Wiechmann and Simone R{\"o}h and Maik K{\"o}del and Torsten Klengel and Darina Czamara and M{\"u}ller, {Nikola S.} and Jari Lahti and Katri R{\"a}ikk{\"o}nen and Pariante, {Carmine M.} and Binder, {Elisabeth B.}",
year = "2019",
month = "8",
day = "9",
doi = "10.1073/pnas.1820842116",
language = "English",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",

}

Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation. / Provençal, Nadine; Arloth, Janine; Cattaneo, Annamaria; Anacker, Christoph; Cattane, Nadia; Wiechmann, Tobias; Röh, Simone; Ködel, Maik; Klengel, Torsten; Czamara, Darina; Müller, Nikola S.; Lahti, Jari; Räikkönen, Katri; Pariante, Carmine M.; Binder, Elisabeth B.

In: Proceedings of the National Academy of Sciences of the United States of America, 09.08.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation

AU - Provençal, Nadine

AU - Arloth, Janine

AU - Cattaneo, Annamaria

AU - Anacker, Christoph

AU - Cattane, Nadia

AU - Wiechmann, Tobias

AU - Röh, Simone

AU - Ködel, Maik

AU - Klengel, Torsten

AU - Czamara, Darina

AU - Müller, Nikola S.

AU - Lahti, Jari

AU - Räikkönen, Katri

AU - Pariante, Carmine M.

AU - Binder, Elisabeth B.

PY - 2019/8/9

Y1 - 2019/8/9

N2 - Prenatal stress exposure is associated with a wide range of health problems later in life. This may be mediated in part via glucocorticoid (GC) exposure during fetal development known to impact neurogenesis and induce epigenetic changes. Using a human fetal hippocampal progenitor cell line to assess the effects of GCs, we observe that exposure to GCs early during neurogenesis results in lasting changes in DNA methylation (DNAm). Lasting DNAm alterations are associated with significantly enhanced transcriptional response to a subsequent GC exposure. Our data suggest that early exposure to GCs changes 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.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.

AB - Prenatal stress exposure is associated with a wide range of health problems later in life. This may be mediated in part via glucocorticoid (GC) exposure during fetal development known to impact neurogenesis and induce epigenetic changes. Using a human fetal hippocampal progenitor cell line to assess the effects of GCs, we observe that exposure to GCs early during neurogenesis results in lasting changes in DNA methylation (DNAm). Lasting DNAm alterations are associated with significantly enhanced transcriptional response to a subsequent GC exposure. Our data suggest that early exposure to GCs changes 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.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.

KW - 3124 Neurology and psychiatry

U2 - 10.1073/pnas.1820842116

DO - 10.1073/pnas.1820842116

M3 - Article

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

ER -