In the case of the array experiments e. Results were then clustered in DAVID to identify enrichment of functional groups using Bonferroni correction for multiple testing. All the data were best fit with a single population model. G1 was Genes related to DNA repair and cell survival were also affected by ethanol and merited further investigation. The greatest change was observed in the gene cluster related to DNA replication enrichment score of Effects of ethanol on cell cycle transcript expression in vitro.
Individual bars represent the fold change in transcript expression following ethanol treatment.
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The expression of 1. Clusters of genes related to cell division enrichment score of Twelve cell cycle genes identified in the microarray studies were selected for verification by qPCR.
Many of the chosen transcripts had multiple functions. Prominent cell cycle genes which are hypermethylated are noted in Table 3. This method allowed for quantitative verification of gene methylation. Within each treatment group, the degree of methylation for selected genes was quantified and standardized to FGF2 samples. In this manner, methylation of a specific gene could be compared for each growth factor in the presence or absence of ethanol. Effects of ethanol on the methylation status of cell cycle genes. These data verify the results of the methylation analysis and demonstrate quantitative increases in the methylation of specific cell cycle genes following ethanol exposure.
These molecules represented the proteins coded by cell cycle transcripts affected by ethanol. This was consistent with the lack of an effect of ethanol on the GF see above. Effects of ethanol on DNA methyltransferase Dnmt protein expression and activity. Right: total Dnmt activity was measured for all four treatment groups. Bars show the mean labeling indices for three samples per treatment. Several transcripts associated with checkpoint regulation were also affected by ethanol exposure, including Cdkn1a p21 , Trp53 , and Mki It is noteworthy that the methyltransferase gene Dnmt1 was also a target of ethanol in vivo.
Effects of ethanol on transcript expression in vivo. Analyses of variance showed a significant effect of ethanol treatment. Ethanol impedes cell cycle progression by increasing the length of the cell cycle, not by reducing the number of cycling cells or inducing cell differentiation. The target of this effect is the G1 phase.
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For example, the proliferation of NSCs in the cortical VZ is depressed by ethanol, whereas the proliferation of progenitors in the cortical subventricular zone and in the subgranular zone of the dentate gyrus can be stimulated by ethanol Miller and Nowakowski ; Miller ; Siegenthaler and Miller a. Ethanol induces an increase in the proportion of NSCs expressing Dnmt1 and the enzymatic activity of all Dnmts.
Such gene silencing is strategic and efficacious. This prevents unwanted cell division and conserves transcriptional machinery for other activities such as apoptosis, differentiation, or cellular repair. The present study shows that DNA hypermethylation is a mechanism by which ethanol can alter cell cycle progression.
In light of such inhibitory effects by ethanol on DNA methylation, specific increases in the methylation of cell cycle genes in the present study are even more impressive. NSCs can employ methylation as a mechanism for altering gene expression in response to external environmental cues Hsieh and Gage Downstream of epigenetic alterations, the effects of ethanol on transcripts expressed by NSCs are quite specific.
For example, in the prefrontal cortices of adult humans with alcohol use disorder, the cell cycle cluster containing the greatest number of differentially expressed genes overlaps with the genes identified in the present study, including Cdc2a. Note that the studies cited above examine whole brain or large brain structures, whereas the present study focuses on actively cycling NSCs.graphicar.dev3.develag.com
Cell-Cycle Mechanisms and Neuronal Cell Death
Cdk1 and Racgap1. Thus, the effects of ethanol on Dnmt transcript diametrically diverge from those on protein and enzymatic activity. Mcm and E2F genes are also specifically hypermethylated following ethanol exposure. The p21 pathway can be affected by growth factors. Thus, through a cascade of downstream molecular changes, there are reductions in protein expression, checkpoint activation, and impeded NSC proliferation. Table S1. As a service to our authors and readers, this journal provides supporting information supplied by the authors.
Technical support issues arising from supporting information other than missing files should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries other than missing content should be directed to the corresponding author for the article. Volume , Issue 6.
Cell-Cycle Mechanisms and Neuronal Cell Death
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Michael W. Address correspondence and reprint requests to Michael W. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Abstract J. Figure 1 Open in figure viewer PowerPoint. The labeling index LI for phosphorylated histone H3 pH3 was independently determined.
Figure 2 Open in figure viewer PowerPoint. Gene ontology cluster No. Enrichment analysis compared the annotation composition of significantly altered mRNAs with a default population of background genes employed by DAVID software. Figure 3 Open in figure viewer PowerPoint. Figure 4 Open in figure viewer PowerPoint.
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