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Project description:Maternal infections have been linked to various neuropsychiatric disorders that may later emerge in offspring. 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) are key DNA modifications but their roles in maternal infection remain to be elucidated. It has been documented that Zika virus (ZIKV) infection during pregnancy leads to structural brain defects such as microcephaly in offspring. However, whether and how offspring exposed to maternal ZIKV infection develop neurocognitive complications remain largely unknown. Here we report that ZIKV infection during mouse pregnancy leads to offspring with depression- and anxiety-like behaviors, which are transmitted to the next generation. Single nucleus RNA sequencing in prefrontal cortex (PFC) of ZIKV offspring mice revealed cell type-specific gene dysregulation associated with neuropsychiatric lesions. Genome-wide 5hmC, 5mC, and transcriptome profiling in ZIKV PFC revealed an overall loss of 5hmC and an increase of 5mC in intragenic regions, associated with transcriptional changes in key functional genes. Gain-of-5hmC regions were mainly located in intergenic transposable elements (TEs) coupled with decreased 5mC and dynamic TE expression. These results provide the first 5hmC study in maternal infection and suggest that maternal ZIKV infection remodels methylome and gene expression in offspring mouse brains, contributing to transgenerational behavior changes.
2023-10-25 | GSE240415 | GEO
Project description:Maternal infections have been linked to various neuropsychiatric disorders that may later emerge in offspring. 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) are key DNA modifications but their roles in maternal infection remain to be elucidated. It has been documented that Zika virus (ZIKV) infection during pregnancy leads to structural brain defects such as microcephaly in offspring. However, whether and how offspring exposed to maternal ZIKV infection develop neurocognitive complications remain largely unknown. Here we report that ZIKV infection during mouse pregnancy leads to offspring with depression- and anxiety-like behaviors, which are transmitted to the next generation. Single nucleus RNA sequencing in prefrontal cortex (PFC) of ZIKV offspring mice revealed cell type-specific gene dysregulation associated with neuropsychiatric lesions. Genome-wide 5hmC, 5mC, and transcriptome profiling in ZIKV PFC revealed an overall loss of 5hmC and an increase of 5mC in intragenic regions, associated with transcriptional changes in key functional genes. Gain-of-5hmC regions were mainly located in intergenic transposable elements (TEs) coupled with decreased 5mC and dynamic TE expression. These results provide the first 5hmC study in maternal infection and suggest that maternal ZIKV infection remodels methylome and gene expression in offspring mouse brains, contributing to transgenerational behavior changes.
2023-10-25 | GSE240413 | GEO
Project description:How early life experience is translated into storable epigenetic information leading to behavioral changes remains poorly understood. Here we found that Zika virus (ZIKV) induced-maternal immune activation (MIA) imparts offspring with anxiety- and depression-like behavior. By integrating bulk and single-nucleus RNA sequencing (snRNA-seq) with genome-wide 5hmC (5-hydroxymethylcytosine) profiling and 5mC (5-methylcytosine) profiling in prefrontal cortex (PFC) of ZIKV-affected male offspring mice, we revealed an overall loss of 5hmC and an increase of 5mC levels in intragenic regions, associated with transcriptional changes in neuropsychiatric disorder-related genes. In contrast to their rapid initiation and inactivation in normal conditions, immediate-early genes (IEGs) remain a sustained upregulation with enriched expression in excitatory neurons, which is coupled with increased 5hmC and decreased 5mC levels of IEGs in ZIKV-affected male offspring. Thus, MIA induces maladaptive methylome remodeling in brain and selectively regulates neuronal activity gene methylation linking to emotional behavioral abnormalities in offspring.
| S-EPMC10687003 | biostudies-literature
Project description:Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation
| PRJNA1003534 | ENA
Project description:Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation [5hmc]
| PRJNA1003538 | ENA
Project description:Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation [5mC]
| PRJNA1003537 | ENA
Project description:Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
| S-EPMC6715719 | biostudies-literature
Project description:Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model. Pregnant rhesus monkeys were injected with a modified form of the viral mimic polyI:C (poly ICLC) or saline at the end of the first trimester. Brain tissue was collected from the offspring at 3.5 years and blocks of dorsolateral prefrontal cortex (BA46) were used to analyze neuronal dendritic morphology and spine density using the Golgi-Cox impregnation method. For each case, 10 layer III pyramidal cells were traced in their entirety, including all apical, oblique and basal dendrites, and their spines. We further analyzed somal size and apical dendrite trunk morphology in 30 cells per case over a 30 ?m section located 100±10 ?m from the soma. Compared to controls, apical dendrites of MIA-treated offspring were smaller in diameter and exhibited a greater number of oblique dendrites. These data provide the first evidence that prenatal exposure to MIA alters dendritic morphology in a nonhuman primate MIA model, which may have profound implications for revealing the underlying neuropathology of neurodevelopmental disorders related to maternal infection.
| S-EPMC5671487 | biostudies-literature
Project description:Schizophrenia and autism are thought to result from the interaction between a susceptibility genotype and environmental risk factors. The offspring of women who experience infection while pregnant have an increased risk for these disorders. Maternal immune activation (MIA) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism, making MIA a useful model of the disorders. However, the mechanism by which MIA causes long-term behavioral deficits in the offspring is unknown. Here we show that the cytokine interleukin-6 (IL-6) is critical for mediating the behavioral and transcriptional changes in the offspring. A single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes prepulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring. Moreover, coadministration of an anti-IL-6 antibody in the poly(I:C) model of MIA prevents the PPI, LI, and exploratory and social deficits caused by poly(I:C) and normalizes the associated changes in gene expression in the brains of adult offspring. Finally, MIA in IL-6 knock-out mice does not result in several of the behavioral changes seen in the offspring of wild-type mice after MIA. The identification of IL-6 as a key intermediary should aid in the molecular dissection of the pathways whereby MIA alters fetal brain development, which can shed new light on the pathophysiological mechanisms that predispose to schizophrenia and autism.
| S-EPMC2387067 | biostudies-literature
Project description:ObjectiveMaternal immune activation (MIA) is associated with an increased risk of autism spectrum disorder (ASD) in offspring. Herein, we investigate the altered expression of microRNAs (miRNA), and that of their target genes, in the brains of MIA mouse offspring.MethodsTo generate MIA model mice, pregnant mice were injected with polyriboinosinic:polyribocytidylic acid on embryonic day 12.5. We performed miRNA microarray and mRNA sequencing in order to determine the differential expression of miRNA and mRNA between MIA mice and controls, at 3 weeks of age. We further identified predicted target genes of dysregulated miRNAs, and miRNA-target interactions, based on the inverse correlation of their expression levels.ResultsMice prenatally subjected to MIA exhibited behavioral abnormalities typical of ASD, such as a lack of preference for social novelty and reduced prepulse inhibition. We found 29 differentially expressed miRNAs (8 upregulated and 21 downregulated) and 758 differentially expressed mRNAs (542 upregulated and 216 downregulated) in MIA offspring compared to controls. Based on expression levels of the predicted target genes, 18 downregulated miRNAs (340 target genes) and three upregulated miRNAs (60 target genes) were found to be significantly enriched among the differentially expressed genes. miRNA and target gene interactions were most significant between mmu-miR-466i-3p and Hfm1 (ATP-dependent DNA helicase homolog), and between mmu-miR-877-3p and Aqp6 (aquaporin 6).InterpretationOur results provide novel information regarding miRNA expression changes and their putative targets in the early postnatal period of brain development. Further studies will be needed to evaluate potential pathogenic roles of the dysregulated miRNAs.
| S-EPMC6186947 | biostudies-literature