Adult Phenotypes and Gene Expression in the Brain at Single Cell Resolution After Developmental Alcohol Exposure in Drosophila
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ABSTRACT:
PROVIDER: PRJNA722499 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14253615.fastq.gz | Fastqsanger.gz | |||
| SRR14253616.fastq.gz | Fastqsanger.gz | |||
| SRR14253617.fastq.gz | Fastqsanger.gz | |||
| SRR14253618.fastq.gz | Fastqsanger.gz | |||
| SRR14253619.fastq.gz | Fastqsanger.gz |
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Project description:Fetal alcohol exposure can lead to developmental abnormalities, intellectual disability, and behavioral changes, collectively termed fetal alcohol spectrum disorder (FASD). In 2015, the CDC found that 1 in 10 pregnant women report alcohol use and more than 3 million women in the USA are at risk of exposing their developing baby to alcohol. Identifying genetic risk alleles for FASD is challenging, since time, dose and frequency of exposure are often unknown, and phenotypic manifestations of FASD are diverse and become evident long after exposure. Drosophila melanogaster presents an excellent model to study developmental effects of alcohol exposure, because virtually unlimited numbers of individuals of the same genotype can be reared rapidly and economically under well-controlled environmental conditions without regulatory restrictions. Furthermore, flies exposed to alcohol undergo physiological and behavioral changes that resemble human alcohol-related phenotypes. Flies reared on ethanol-supplemented medium show decreased viability, reduced sensitivity to ethanol, and disrupted sleep and activity patterns. To assess alcohol-modulated gene expression in the brains of flies reared on alcohol, we performed single cell RNA sequencing and resolved cell clusters with differentially expressed genes representing distinct neuronal and glial populations. We observed extensive sexual dimorphism. Two clusters associated with glial biomarkers showed greater differential gene expression in males, whereas mushroom body-derived cells exhibited a greater degree of differential gene expression in females. Results obtained from these studies provide a blueprint for translational studies on alcohol-induced effects on gene expression in the brain that may contribute to or result from FASD in human populations.
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Project description:Prenatal exposure to ethanol can cause fetal alcohol spectrum disorder (FASD), a prevalent and preventable pediatric disorder. Identifying genetic risk alleles for FASD is impossible in human populations, but the Drosophila genetic model can provide insights. We analyzed changes in genome-wide gene expression in 96 wild-derived inbred fly lines after exposure to alcohol during development. We found extensive sexual dimorphism in the effect of alcohol on gene expression along with effects on adult locomotor activity and sleep. Genetic networks associated with changes in gene expression include both protein-coding and non-coding transcripts, including a female-specific module of small nucleolar RNAs that regulate pseudouridylation of ribosomal RNA. These data support a regulatory role for non-coding elements in response to developmental alcohol exposure.
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Project description:Abstinence is an important therapeutic intervention for patients with alcohol-associated liver disease (ALD). However, fibrosis improvement after cessation is not uniform and some patients do not improve. We aimed to use scATAC-seq analysis in a mouse model of ALD to define the mechanism of poor ALD resolution. We analyzed differentially accessible regions in livers from control, ALD, or 4 weeks post alcohol cessation mice and identified transcription factors activated in ALD that remained activated after alcohol withdrawal. The top hit was C/EBPβ. We found that hepatocyte specific Cebpb knockout prevented ALD development, while knockout at the time of alcohol cessation promoted fibrosis resolution.
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Project description:Fetal alcohol exposure at any stage of pregnancy can lead to Fetal Alcohol Spectrum Disorder (FASD), a group of life-long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8-cell stage) fetal alcohol exposure in mice leads to long-term FASD-like morphological phenotypes (e.g., growth restriction, brain malformations, skeletal delays) in late-gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol-induced morphological defects without altering DNA methylation status and regulation of imprinting control regions. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizing the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.
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Project description:Prenatal alcohol exposure is recognized to alter DNA methylation profiles of brain cells during development, and as being part of the molecular basis underpinning Fetal Alcohol Spectrum Disorder (FASD) etiology. However, we have negligible information on the effects of alcohol during the initial embryonic stages, a window marked with dynamic DNA methylation reprogramming, and on how this may rework the brain developmental program. Using a pre-clinical in vivo mouse model, we show that pre-implantation alcohol exposure leads to adverse developmental outcomes that replicate clinical facets observed in children with FASD. Genome-wide DNA methylation analyses of fetal forebrains uncovered sex-specific alterations, including partial loss of DNA methylation maintenance at imprinted control regions, and abnormal re-establishment of de novo DNA methylation profiles in various biological pathways (e.g, neural/brain development). These findings support the contribution of alcohol-induced DNA methylation programming deviations during pre-implantation to the manifestations of neurodevelopmental phenotypes associated with FASD.
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Project description:Fetal alcohol exposure can lead to developmental abnormalities, intellectual disability, and behavioral changes, collectively termed fetal alcohol spectrum disorder (FASD). In 2015, the Centers for Disease Control found that 1 in 10 pregnant women report alcohol use and more than 3 million women in the USA are at risk of exposing their developing fetus to alcohol. Drosophila melanogaster is an excellent genetic model to study developmental effects of alcohol exposure because many individuals of the same genotype can be reared rapidly and economically under controlled environmental conditions. Flies exposed to alcohol undergo physiological and behavioral changes that resemble human alcohol-related phenotypes. Here, we show that adult flies that developed on ethanol-supplemented medium have decreased viability, reduced sensitivity to ethanol, and disrupted sleep and activity patterns. To assess the effects of exposure to alcohol during development on brain gene expression, we performed single cell RNA sequencing and resolved cell clusters with differentially expressed genes which represent distinct neuronal and glial populations. Differential gene expression showed extensive sexual dimorphism with little overlap between males and females. Gene expression differences following developmental alcohol exposure were similar to previously reported differential gene expression following cocaine consumption, suggesting that common neural substrates respond to both drugs. Genes associated with glutathione metabolism, lipid transport, glutamate and GABA metabolism, and vision feature in sexually dimorphic global multi-cluster interaction networks. Our results provide a blueprint for translational studies on alcohol-induced effects on gene expression in the brain that may contribute to or result from FASD in human populations.
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Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Recently we identified hepatic demethylases KDM5B and KDM5C as important sex-specific epigenetic regulators of alcohol response in the liver. In this study we aimed to study the molecular mechanisms of KDM5-dependent ALD development and resolution. We found that alcohol induces pathological changes in cell-cell communication in the liver that are in part mediated by epigenetic changes in hepatocytes mediated by histone demethylase KDM5B. Using cell type specific knockout mice, we found that KDM5B histone demethylase was a key regulator of alcohol-induced epigenetic changes in hepatocytes. Moreover, it regulated hepatocytes-non-parenchymal cell crosstalk that promoted inflammation and fibrosis development in ALD. This mechanism was specific to females. In males KDM5B deficiency was not sufficient to prevent fibrosis development. In contrast KDM5B demethylase loss promoted fibrosis resolution in both males and females. This mechanism involved changes in hepatocyte-macrophage crosstalk and LXRα activation, which we identified to be critical for the fibrosis resolution process. CONCLUSION: In summary, KDM5B demethylase is a regulator of cell-cell crosstalk involved in disease progression in females and in disease resolution in both sexes.
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Project description:Glial cells are central players in the pathogenesis of neurodevelopmental disorders like Fetal Alcohol Spectrum Disorder (FASD). Ethanol can modulate glial differentiation and astrocyte function imposing dramatic changes to the developing brain. Since ethanol can affect a vast number of intracellular targets and signaling pathways and many effects of early alcohol exposure on cell physiology can persist into adulthood, we tested the hypothesis that ethanol exposure in ferrets during a period equivalent to the last months of human gestation leads to a long-lasting change in astrocyte secretome in vitro. Animals were treated every other day with ethanol (5g/kg) or saline between post-natal day (P)10-30. At P31, astrocyte cultures were made and cells were submitted to stable isotope labeling by amino acids (SILAC). 24h-conditioned media of cells obtained from ethanol- or saline-treated animals (ET-CM or SAL-CM) were collected and analyzed by quantitative mass spectrometry in tandem with liquid chromatography. Here we show that 65 out of 280 quantifiable proteins displayed significant differences comparing ET-CM to SAL-CM. Among 59 proteins found reduced in ET-CM we found components of the extracellular matrix like Laminin subunits α2, α4, β1, β2 and γ1 and the proteoglycans Biglycan, Heparin Sulfate Proteoglycan 2 and Lumican. Proteins with trophic function like Insulin-Like Growth Factor Binding Protein 4, Pigment Epithelium-Derived Factor and Clusterin as well as proteins involved on modulation of proteolysis like TIMP-1 and PAI-1 were also found reduced. On the other hand, pro-synaptogeneic proteins like Thrombospondin-1, Hevin as well as the modulator of extracelular matrix expression, Angiotensinogen, were found increased in ET-CM. The analysis of interactome maps through Ingenuity Pathway Analysis demonstrated that the Amyloid beta A4 protein precursor (APP), which was found reduced in ET-CM, was previously shown to interact with ten other proteins that exhibited significant changes in the ET-CM, rendering it a suitable target for a more accurate analysis about the effects of ethanol on its biology. Taken together our results strongly suggest that early exposure to teratogens such alcohol may lead to an enduring change in astrocyte secretome, affecting mainly the expression of trophic and matricellular proteins, which in turn may lead to permanent alterations in brain function.
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