Epigenetic changes at gene promoters in response to immune activation in utero
Abstract
Increasing evidence suggests that maternal infection increases the risk of psychiatric disorders, such as schizophrenia and autism in offspring. However, the molecular mechanisms associated with these effects are unclear. Here, we have studied epigenetic gene regulation in mice exposed to non-specific immune activation elicited by polyI:C injection to pregnant dams. Using Western blot analysis, we detected global hypoacetylation of histone H3, at lysine residues 9 and 14, and histone H4, at lysine residue 8, in the cortex from juvenile (∼24days of age) offspring exposed to polyI:C in utero, but not from adult (3months of age) offspring, which exhibit significant behavioral abnormalities. Accordingly, we detected robust deficits in the expression of genes associated with neuronal development, synaptic transmission and immune signaling in the cortex of polyI:C-exposed juvenile mice. In particular, we found that several genes in the glutamate receptor signaling pathway, including Gria1 and Slc17a7, showed decreases in promoter-specific histone acetylation, and corresponding gene expression deficits, in polyI:C-exposed offspring at both juvenile and adult ages. In contrast, the expression of these same genes, in addition to Disc1 and Ntrk3, was elevated in the hippocampus of juvenile mice, in concordance with elevated levels of promoter-specific histone acetylation. We suggest that these early epigenetic changes contribute to the delayed behavioral abnormalities that are observed in adult animals after exposure to polyI:C, and which resemble symptoms seen in schizophrenia and related disorders.
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Inflammatory mediators such as cytokines induce alterations during neurodevelopment by histone modifications, methylation changes at the promoter of ASD-critical genes such as MECP2 or genes involved in synaptic functions, and global methylation changes.
“Inflammatory mediators (e.g., cytokines) induce such alterations during neurodevelopment [138] by histone modifications [139], methylation changes at the promoter of ASD-critical genes (e.g., MECP2) [140] or genes involved in synaptic functions [141] and global methylation changes [136].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [139]
Offspring born to mothers injected with LPS or poly(I:C) during pregnancy showed decreases in promoter-specific histone acetylation and corresponding gene expression.
“offspring born to mothers injected with LPS or poly(I:C) during pregnancy, showed decreases in promotor-specific histone acetylation and corresponding gene expression (Tang et al., 2013).”
From Neuroinflammation as a risk factor for attention deficit hyperactivity disorder (2019) · cites this paper as Tang et al., 2013
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- Authors
- Tang, B., Jia, H., Kast, R. J., & Thomas, E. A.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Thomas, Elizabeth A.
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 30
- Pages
- 168-175
- ISSN
- 0889-1591 (ISSN-L)
- OpenAlex
- W2068874168
- Cited by
- 91
- References
- 59
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 7 · 2016: 12 · 2015: 8 · 2014: 5 · 2013: 5
- FWCI
- 3.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- maternal immune activation, poly(I:C), histone acetylation, histone H3, histone H4, cortical gene expression, glutamate receptor signaling, GluR1, VGLUT1, DISC1, NTRK3, hippocampus, schizophrenia, autism spectrum disorder, mental illness, offspring behavior
- MeSH terms
- Animals, Behavior, Animal, Female, Gene Expression Regulation, Hippocampus, Male, Poly I-C, Pregnancy, Prenatal Exposure Delayed Effects, Promoter Regions, Genetic, Schizophrenia, Epigenesis, Genetic, Mice
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