Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements.
- Authors
- Liyanage, Vichithra Rasangi Batuwita; Zachariah, Robby Mathew; Davie, James Ronald; Rastegar, Mojgan
- Year
- 2015
- Journal
- Experimental neurology
- PMID
- 25620416
- DOI
- 10.1016/j.expneurol.2015.01.006
- PMCID
- PMC5798977
Methyl CpG Binding Protein 2 (MeCP2) is an important epigenetic factor in the brain. MeCP2 expression is affected by different environmental insults including alcohol exposure. Accumulating evidence supports the role of aberrant MeCP2 expression in ethanol exposure-induced neurological symptoms. However, the underlying molecular mechanisms of ethanol-induced MeCP2 deregulation remain elusive. To study the effect of ethanol on Mecp2/MeCP2 expression during neurodifferentiation, we established an in vitro model of ethanol exposure, using differentiating embryonic brain-derived neural stem cells (NSC). Previously, we demonstrated the impact of DNA methylation at the Mecp2 regulatory elements (REs) on Mecp2/MeCP2 expression in vitro and in vivo. Here, we studied whether altered DNA methylation at these REs is associated with the Mecp2/MeCP2 misexpression induced by ethanol. Binge-like and continuous ethanol exposure upregulated Mecp2/MeCP2, while ethanol withdrawal downregulated its expression. DNA methylation analysis by methylated DNA immunoprecipitation indicated that increased 5-hydroxymethylcytosine (5hmC) and decreased 5-methylcytosine (5mC) enrichment at specific REs were associated with upregulated Mecp2/MeCP2 following continuous ethanol exposure. The reduced Mecp2/MeCP2 expression upon ethanol withdrawal was associated with reduced 5hmC and increased 5mC enrichment at these REs. Moreover, ethanol altered global DNA methylation (5mC and 5hmC). Under the tested conditions, ethanol had minimal effects on NSC cell fate commitment, but caused changes in neuronal morphology and glial cell size. Taken together, our data represent an epigenetic mechanism for ethanol-mediated misexpression of Mecp2/MeCP2 in differentiating embryonic brain cells. We also show the potential role of DNA methylation and MeCP2 in alcohol-related neurological disorders, specifically Fetal Alcohol Spectrum Disorders.
No figures extracted from this document.
No chunks — full text not yet ingested.
No entities extracted from this document yet.
No uploaded files.
No citations found.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Ethanol Alters DNMT1/3a/3b Expression Profile, Promotes Persistent DNA Hypomethylation in Human Brain Endothelial Cells and Impairs Late Cortical Angiogenesis. | Siqueira M et al. | — | 2026 | → |
| The role of DNA methylation in alcohol-mediated neurodevelopmental toxicity. | Gao J et al. | — | 2026 | → |
| Effects of alcohol on the transcriptome, methylome and metabolome of in vitro gastrulating human embryonic cells. | Wallén E et al. | — | 2025 | → |
| Nonconceptus Mechanisms of Prenatal Alcohol Exposure That Disrupt Embryo-Fetal Development: An Integrative View. | Smith SM | — | 2025 | → |
| Rett syndrome: Pathogenicity and regulation of MECP2 (human) and Mecp2 (mouse) genes and their protein products through various molecular mechanisms. | Ahmad B et al. | — | 2025 | → |
| Reciprocal crosslink among MeCP2/BDNF /CREB signaling pinpointed in autism spectrum disorder. | Mahmoud AH et al. | — | 2024 | → |
| MeCP2 Is an Epigenetic Factor That Links DNA Methylation with Brain Metabolism. | Vuu YM et al. | — | 2023 | → |
| The Epigenetic Reader Methyl-CpG-Binding Protein 2 (MeCP2) Is an Emerging Oncogene in Cancer Biology. | Nejati-Koshki K et al. | — | 2023 | → |
| Differential Sensitivity of the Protein Translation Initiation Machinery and mTOR Signaling to <i>MECP2</i> Gain- and Loss-of-Function Involves MeCP2 Isoform-Specific Homeostasis in the Brain. | Buist M et al. | — | 2022 | → |
| The Chromatin Structure at the <i>MECP2</i> Gene and In Silico Prediction of Potential Coding and Non-Coding <i>MECP2</i> Splice Variants. | Shevkoplyas D et al. | — | 2022 | → |
| Pre-implantation alcohol exposure induces lasting sex-specific DNA methylation programming errors in the developing forebrain. | Legault LM et al. | — | 2021 | → |
| Role of DNA Methyl-CpG-Binding Protein MeCP2 in Rett Syndrome Pathobiology and Mechanism of Disease. | Pejhan S et al. | — | 2021 | → |
| The Effects of Early Prenatal Alcohol Exposure on Epigenome and Embryonic Development. | Wallén E et al. | — | 2021 | → |
| Transcriptional Regulation of <i>MECP2E1-E2</i> Isoforms and <i>BDNF</i> by Metformin and Simvastatin through Analyzing Nascent RNA Synthesis in a Human Brain Cell Line. | Buist M et al. | — | 2021 | → |
| Chronic Ethanol Exposure Alters DNA Methylation in Neural Stem Cells: Role of Mouse Strain and Sex. | Amiri S et al. | — | 2020 | → |
| Differential brain region-specific expression of MeCP2 and BDNF in Rett Syndrome patients: a distinct grey-white matter variation. | Pejhan S et al. | — | 2020 | → |
| Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine. | Efimova OA et al. | — | 2020 | → |
| Pre-Implantation Alcohol Exposure Induces Lasting Sex-Specific DNA Methylation Programming Errors in the Developing Forebrain | Legault L et al. | — | 2020 | — |
| Regulation, diversity and function of MECP2 exon and 3'UTR isoforms. | Rodrigues DC et al. | — | 2020 | → |
| The MeCP2E1/E2-BDNF-<i>miR132</i> Homeostasis Regulatory Network Is Region-Dependent in the Human Brain and Is Impaired in Rett Syndrome Patients. | Pejhan S et al. | — | 2020 | → |
| DNA Methylation Contributes to the Differential Expression Levels of <i>Mecp2</i> in Male Mice Neurons and Astrocytes. | Liyanage VRB et al. | — | 2019 | → |
| Fetal alcohol spectrum disorder (FASD) affects the hippocampal levels of histone variant H2A.Z-2. | Gretzinger TL et al. | — | 2019 | → |
| Genome-Wide Transcriptome Landscape of Embryonic Brain-Derived Neural Stem Cells Exposed to Alcohol with Strain-Specific Cross-Examination in BL6 and CD1 Mice. | Xu W et al. | — | 2019 | → |
| Simvastatin Induces Apoptosis in Medulloblastoma Brain Tumor Cells via Mevalonate Cascade Prenylation Substrates. | Sheikholeslami K et al. | — | 2019 | → |
| Atypical fetal development: Fetal alcohol syndrome, nutritional deprivation, teratogens, and risk for neurodevelopmental disorders and psychopathology. | Georgieff MK et al. | — | 2018 | → |
| CB1R-Mediated Activation of Caspase-3 Causes Epigenetic and Neurobehavioral Abnormalities in Postnatal Ethanol-Exposed Mice. | Subbanna S et al. | — | 2018 | → |
| DNA methylation signatures: Biomarkers of drug and alcohol abuse. | Mahna D et al. | — | 2018 | → |
| Epigenetic mechanisms in alcohol- and adversity-induced developmental origins of neurobehavioral functioning. | Boschen KE et al. | — | 2018 | → |
| Epigenetic Regulations in Neural Stem Cells and Neurological Diseases. | Zhou H et al. | — | 2018 | → |
| <i>MECP2</i> Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients. | Olson CO et al. | — | 2018 | → |
| Prenatal Alcohol Exposure: Profiling Developmental DNA Methylation Patterns in Central and Peripheral Tissues. | Lussier AA et al. | — | 2018 | → |
| Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure. | Gavin DP et al. | — | 2017 | → |
| DNA Methylation program in normal and alcohol-induced thinning cortex. | Öztürk NC et al. | — | 2017 | → |
| DNA modifications in models of alcohol use disorders. | Tulisiak CT et al. | — | 2017 | → |
| Editorial (Thematic Issue: NeuroEpigenetics and Neurodevelopmental Disorders: From Molecular Mechanisms to Cell Fate Commitments of the Brain Cells and Human Disease). | Rastegar M | — | 2017 | → |
| Epigenetics studies of fetal alcohol spectrum disorder: where are we now? | Lussier AA et al. | — | 2017 | → |
| Bioinformatic Analysis of DNA Methylation in Neural Progenitor Cell Models of Alcohol Abuse. | Oni EN et al. | — | 2016 | → |
| DNA cytosine hydroxymethylation levels are distinct among non-overlapping classes of peripheral blood leukocytes. | Hohos NM et al. | — | 2016 | → |
| Ethanol-mediated activation of the NLRP3 inflammasome in iPS cells and iPS cells-derived neural progenitor cells. | De Filippis L et al. | — | 2016 | → |
| Interactions between Early Life Stress, Nucleus Accumbens MeCP2 Expression, and Methamphetamine Self-Administration in Male Rats. | Lewis CR et al. | — | 2016 | → |