The Genomic Architecture of Pregnancy-Associated Plasticity in the Maternal Mouse Hippocampus
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ABSTRACT:
PROVIDER: PRJNA815312 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18301861_1.fastq.gz | Fastqsanger.gz | |||
| SRR18301861_2.fastq.gz | Fastqsanger.gz | |||
| SRR18301862_1.fastq.gz | Fastqsanger.gz | |||
| SRR18301862_2.fastq.gz | Fastqsanger.gz | |||
| SRR18301863_1.fastq.gz | Fastqsanger.gz |
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Project description:We performed single nucleus RNA-seq and single nucleus ATAC-seq from the mouse hippocampus before, during, and after pregnancy.
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Project description:The evolution of human diets led to preferences towards polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in w-6 PUFA1. Mounting evidence points to w-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans2. When chosen during pregnancy, w-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus2,3. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine w-6 PUFA excess3, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional w-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity once exposing mouse fetuses to excess w-6 PUFAs in utero. Conversion of w-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates with DNA methylome analysis and ATAC-seq uncovering epigenetic reprogramming at >1,400 sites in neurons after prolonged cannabinoid exposure. We find anxiety and depression-like behavioral traits to manifest in adult offspring, which is compatible with genetic models of reduced IgCAM expression to suggest causality to cortical wiring defects4. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit the offsprings’ brain function for life.
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Project description:Life-long epigenetic programming of cortical architecture by maternal Western diet during pregnancy
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Project description:Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy [RRBS]
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Project description:Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programming of the fetal brain in the absence of maternal obesity or maternal undernutrition is a lesser-explored area. The goal of this study was to investigate the impact of two different maternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal behavior in a mouse model. Female C57Bl/6J mice were fed one of two commercially-available chow diets (pelleted vs. powdered) with differing micronutrient and carbohydrate compositions throughout pregnancy and lactation. The powdered chow diet was richer in carbohydrates and lower in micronutrients than the pelleted chow diet, among other differences. On embryonic day 15.5, embryos were weighed and measured. Fetal brains were snap frozen. RNA was extracted from fetal forebrains for five fetuses per diet group and hybridized to whole genome expression microarrays. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, humoral and cell-mediated immune response, carbohydrate and lipid metabolism, small molecule biosynthesis, and amino acid metabolism were also dysregulated. Maternal dietary content is an important variable for researchers evaluating fetal brain development and offspring behavior to consider. Selection of a chow diet matched for micronutrients is crucial to avoid unexpected or undesired effects on offspring brain development and behavior.
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Project description:Metabolic variations occur during normal pregnancy to provide the growing fetus with a supply of nutrients required for its development and to ensure the health of the woman during gestation. Mass spectrometry-based metabolomics was employed to study the metabolic phenotype variations in the maternal plasma that are induced by pregnancy in each of its three trimesters. Nontargeted metabolomics analysis showed that pregnancy significantly altered the profile of metabolites in maternal plasma. The levels of six metabolites were found to change significantly throughout pregnancy, with related metabolic pathway variations observed in biopterin metabolism, phospholipid metabolism, amino acid derivatives, and fatty acid oxidation. In particular, there was a pronounced elevation of dihydrobiopterin (BH2), a compound produced in the synthesis of dopa, dopamine, norepinephrine, and epinephrine, in the second trimester, whereas it was markedly decreased in the third trimester. The turnover of BH2 and tryptophan catabolites indicated that the fluctuations of neurotransmitters throughout pregnancy might reveal the metabolic adaption in the maternal body for the growth of the fetus. Furthermore, 11 lipid classes and 41 carnitine species were also determined and this showed variations in the presence of long-chain acylcarnitines and lysophospholipids in later pregnancy, suggesting changes of acylcarnitines and lysophospholipids to meet the energy demands in pregnant women.
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Project description:Life-long epigenetic programming of cortical architecture by maternal 'Western' diet during pregnancy [ATAC-seq]
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Project description:The functional output of the hippocampus, a brain region subserving memory processes, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular processes involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role in the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. We find that TIMP2 regulates accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in migration of newborn neurons through a denser ECM network. A conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.
2023-11-02 | GSE223188 | GEO
Project description:The evolution of human diets led to preferences towards polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1,400 sites in neurons after prolonged cannabinoid exposure. We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring’s brain function for life.
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