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Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation [5hmc]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE240415 | GEO | 2023/10/25

REPOSITORIES: GEO

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Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation [5mC]

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

MeDIP and hMeDIP assays using human placentas of obese and lean (healthy weight) pregnancies

Project description:Maternal obesity has both a direct effect on the outcome of pregnancy but also programs the fetus for obesity and metabolic syndrome in later life. Due to its roles at the interface between mother and fetus, the placenta transduces and mediates the effects of the obese intrauterine environment on the fetus. Here we have generated genome-scale high-resolution maps of 5mC and 5hmC in human placentas of obese and healthy weight pregnancies. Widespread alterations to the placental epigenome identified across the genome in the setting of maternal adiposity are primarily characterized by increase in 5mC and reciprocal decrease in 5hmC. This is also evident at the two pregnancy-associated gene clusters on chromosomes 17 and 19. In addition, maternal adiposity is associated with downregulation of ten-eleven translocation (TET) and isocitrate dehydrogenase (IDH) family genes and is accompanied by decreased levels of Î±-ketoglutarate (Î±KG) in the placenta. Of note, Î±KG levels exhibit a close positive correlation with both ascorbate and aconitate levels and less substantial but significant association with global 5hmC levels and placenta-specific gene expression. These observations suggest a mechanistic linkage between obesogenic environment and conversion efficiency of 5mC to 5hmC and highlight the idea that TET-mediated active DNA demethylation pathway can sense and respond to metabolic derangements and plays a role in subsequent cellular adaptation. Collectively, this study demonstrates that altered DNA demethylation process is likely one of the mechanisms underlying metabolic modulation of the placental epigenome with maternal adiposity. Comparison of lean vs obese epigenomes in human pregnancies

2017-05-04 | E-GEOD-69769 | biostudies-arrayexpress

Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts

Project description:Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be differentiated into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

2022-05-20 | PXD033289 | Pride

Rhesus macaque early-gestation trophoblast cells are permissive to Zika virus infection and viral exposure altered extracellular vesicle cargo

Project description:Zika virus (ZIKV) infection of maternal and placental cells at the maternal-fetal interface is associated with a spectrum of adverse pregnancy outcomes including fetal demise and pregnancy loss. Trophoblast cell types that comprise the placenta include cytotrophoblasts, syncytiotrophoblasts (STs), and extravillous trophoblasts (EVTs). To determine which trophoblast cells are permissive to ZIKV and to understand how infection impacts cellular gene expression, we utilized a macaque in vitro trophoblast stem cell (TSC) model. TSCs were derived from primary cytotrophoblasts and represent a proliferative trophoblast that can be differentiated into STs and EVTs. TSCs and ST3Ds (STs grown in suspension) were highly permissive to infection with ZIKV strain DAK AR 41524, whereas EVTs maintained a level of resistance to productive infection. The impact of ZIKV on cellular gene expression was determined by transcriptomic and miRNAome analysis. Infection of TSCs and ST3Ds results in increased expression of immune related genes, including those in the type I and type III interferon response. ZIKV exposure impacts EV protein, mRNA, and miRNA cargo, regardless of productive infection. Altogether, these findings suggest TSCs and STs of the macaque are permissive to ZIKV infection and that EV analysis has the potential to identify ZIKV infection. These findings provide a foundation for further ZIKV study and allow for potential ZIKV infection biomarker identification in a highly translational model.

2022-01-01 | GSE185113 | GEO

Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts [miRNA-seq]

Project description:Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be directed to differentiate into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

2022-01-10 | GSE193195 | GEO

Zika virus impacts extracellular vesicle composition and cellular gene expression in macaque early gestation trophoblasts

Project description:Zika virus (ZIKV) infection at the maternal-placental interface is associated with adverse pregnancy outcomes including fetal demise and pregnancy loss. To determine how infection impacts placental trophoblasts, we utilized rhesus macaque trophoblast stem cells (TSC) that can be directed to differentiate into early gestation syncytiotrophoblasts (ST) and extravillous trophoblasts (EVT). TSCs and STs, but not EVTs, were highly permissive to productive infection with ZIKV strain DAK AR 41524. The impact of ZIKV on the cellular transcriptome showed that infection of TSCs and STs increased expression of immune related genes, including those involved in type I and type III interferon responses. ZIKV exposure altered extracellular vesicle (EV) protein, mRNA, and miRNA cargo, regardless of productive infection. These findings suggest that early gestation macaque TSCs and STs are permissive to ZIKV infection, and that EV analysis may provide a foundation for identifying non-invasive biomarkers of placental infection in a highly translational model.

2022-01-01 | GSE185291 | GEO

MeDIP and hMeDIP assays using human placentas of obese and lean (healthy weight) pregnancies

Project description:Maternal obesity has both a direct effect on the outcome of pregnancy but also programs the fetus for obesity and metabolic syndrome in later life. Due to its roles at the interface between mother and fetus, the placenta transduces and mediates the effects of the obese intrauterine environment on the fetus. Here we have generated genome-scale high-resolution maps of 5mC and 5hmC in human placentas of obese and healthy weight pregnancies. Widespread alterations to the placental epigenome identified across the genome in the setting of maternal adiposity are primarily characterized by increase in 5mC and reciprocal decrease in 5hmC. This is also evident at the two pregnancy-associated gene clusters on chromosomes 17 and 19. In addition, maternal adiposity is associated with downregulation of ten-eleven translocation (TET) and isocitrate dehydrogenase (IDH) family genes and is accompanied by decreased levels of α-ketoglutarate (αKG) in the placenta. Of note, αKG levels exhibit a close positive correlation with both ascorbate and aconitate levels and less substantial but significant association with global 5hmC levels and placenta-specific gene expression. These observations suggest a mechanistic linkage between obesogenic environment and conversion efficiency of 5mC to 5hmC and highlight the idea that TET-mediated active DNA demethylation pathway can sense and respond to metabolic derangements and plays a role in subsequent cellular adaptation. Collectively, this study demonstrates that altered DNA demethylation process is likely one of the mechanisms underlying metabolic modulation of the placental epigenome with maternal adiposity.

2017-05-04 | GSE69769 | GEO

Maternal immune activation by LPS selectively alters specific gene expression profiles of interneuron migration and oxidative stress in the fetus without triggering a fetal immune response.

Project description:Maternal immune activation is a risk factor for the development of schizophrenia and autism. Infections during pregnancy activate the mother's immune system and alter the fetal environment with sub-sequence effects of CNS function and behavior in the offspring, but the cellular and molecular links between infection-induced altered fetal development and risk for neuropsychiatric disorders are unknown. We investigated the immunological, molecular, and behavioral effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on embryonic day 15. LPS significantly elevated pro-inflammatory cytokines in maternal serum, amniotic fluid, and fetal brain at 4 h, and levels decreased but remained elevated at 24 h. Offspring born to LPS-dams exhibited reduced social and exploration behaviors as juveniles and young adults. Whole genome microarray analysis of the fetal brain at 4 h post maternal LPS was performed to elucidate possible molecular mechanisms by which MIA effects the fetal brain. We observed dysregulation of 3,285 genes in restricted functional categories, with increased mRNA expression of cellular stress and cell death genes and reduced expression of developmentally-regulated and brain-specific genes, specifically those that regulate neuronal migration of GABAergic interneurons. 19 Fetal Rat Brain Samples: 10 (-) LPS, 9 (+) LPS.

2012-07-25 | E-GEOD-34058 | biostudies-arrayexpress

Effect of ZIKV on pre-implantation embryos

Project description:To determine the effect of Zika virus infection on pre-implantation embryonic development, we performed single blastocyst RNA-Seq on MOCK and ZIKV infected embryos. ZIKV infection results in an increased risk of spontaneous abortion and poor intrauterine growth although the mechanisms underlying fetal loss remain undetermined. Little is known about the impact of ZIKV infection during the earliest stages of pregnancy, or pre- and peri-implantation, because most current studies of ZIKV infection in pregnancy models focus on post-implantation stages. Here, we demonstrate that trophectoderm cells of pre-implantation human and mouse embryos can be efficiently infected with ZIKV, and that trophectoderm can propagate virus causing cell death of neural progenitors. These findings were corroborated by our demonstration that hESC-derived trophectoderm cells are infected by ZIKV in a dose dependent manner. RNAseq of single blastocysts revealed key transcriptional changes in cellular and physiologic functions upon ZIKV infection, including nervous system development and function, prior to commitment to the neural cell lineage. Finally, the pregnancy rate of mice infected pre-implantation was > 50% lower than females infected at E4.5. These results demonstrate that pre-implantation ZIKV infection of trophectoderm leads to miscarriage or spontaneous abortion. Moreover, pre- and peri-implantation ZIKV infects trophectoderm cells that propagate virus over time causing cell death in neural progenitors. Cumulatively, these data demonstrate that vertical pre- and peri-implantation ZIKV infection of trophectoderm impairs fetal development and causes neural progenitor cell death, elucidating a previously unappreciated association of pre- and peri-implantation ZIKV infection and microcephaly.

2019-08-16 | GSE133254 | GEO

Persistent transcriptomic alterations in medial prefrontal cortex after prenatal exposure to maternal inflammation

Project description:Infection during pregnancy is strongly implicated as an environmental risk factor for autism spectrum disorder (ASD), with activation of the maternal immune system (MIA) identified in the causative pathway. Maternal exposure to viral and bacterial mimics at midgestation leads to the development of core ASD behaviors in rodent offspring. However, the fundamental pathogenic mechanisms coupling MIA to persistent changes in brain function and behavior are incompletely understood.The medial prefrontal cortex (mPFC) is a major locus of pathology in ASD and highly associated with behaviors dysregulated by MIA. Transcriptomic profiling of the mPFC from adult MIA and control offspring provides insight into molecular pathways persistently disrupted by prenatal exposure to maternal inflammation.

2018-07-26 | GSE117327 | GEO

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