Epigenetics and pharmacology

Stefańska, Barbara; MacEwan, David J.

doi:10.1111/bph.13136

Cited by 21 publications

(8 citation statements)

References 17 publications

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“…In our dual luminescence reporter test system, the HDAC inhibitors shared similarities but also showed distinct features. Consistent with the role of histone acetylation in epigenetic regulation (Stefanska and MacEwan 2015; Varela et al 2013), all HDAC inhibitors led to some degree of enhanced reporter activity. However, distinct features were the preferential effects in either ESCs as compared to neurons.…”

Section: Resultssupporting

confidence: 70%

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

et al. 2016

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Identification of neurotoxic drugs and environmental chemicals is an important challenge. However, only few tools to address this topic are available. The aim of this study was to develop a neurotoxicity/developmental neurotoxicity (DNT) test system, using the pluripotent mouse embryonic stem cell line CGR8 (ESCs). The test system uses ESCs at two differentiation stages: undifferentiated ESCs and ESC-derived neurons. Under each condition, concentration–response curves were obtained for three parameters: activity of the tubulin alpha 1 promoter (typically activated in early neurons), activity of the elongation factor 1 alpha promoter (active in all cells), and total DNA content (proportional to the number of surviving cells). We tested 37 compounds from the ESNATS test battery, which includes polypeptide hormones, environmental pollutants (including methylmercury), and clinically used drugs (including valproic acid and tyrosine kinase inhibitors). Different classes of compounds showed distinct concentration–response profiles. Plotting of the lowest observed adverse effect concentrations (LOAEL) of the neuronal promoter activity against the general promoter activity or against cytotoxicity, allowed the differentiation between neurotoxic/DNT substances and non-neurotoxic controls. Reporter activity responses in neurons were more susceptible to neurotoxic compounds than the reporter activities in ESCs from which they were derived. To relate the effective/toxic concentrations found in our study to relevant in vivo concentrations, we used a reverse pharmacokinetic modeling approach for three exemplary compounds (teriflunomide, geldanamycin, abiraterone). The dual luminescence reporter assay described in this study allows high-throughput, and should be particularly useful for the prioritization of the neurotoxic potential of a large number of compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1690-2) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 70%

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

et al. 2016

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“…A growing number of data confirmed that microRNAs play a crucial role in the regulation of gene expression via control of post-transcriptional mRNA function. As “global-regulators” miRNAs direct a diverse range of cellular responses both in normal and pathological conditions [ 20 , 34 ]. Expression of miRNA is one of the universal epigenetic mechanisms implicated in the regulation of growth and survival pathways in cancer cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic control of phospholipase A2 receptor expression in mammary cancer cells

et al. 2015

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BackgroundIt has recently been proposed that the M-type phospholipase A2 receptor (PLA2R1) acts as a tumour suppressor in certain malignancies including mammary cancer. Considering that DNA methylation is an important regulator of gene transcription during carcinogenesis, in the current study we analyzed the PLA2R1 expression, PLA2R1 promoter methylation, and selected micro RNA (miRNA) levels in normal human mammary epithelial cells (HMEC) and cancer cell lines.MethodsLevels of PLA2R1 and DNA methyltransferases (DNMT) specific mRNA were determined using real-time RT-PCR. Methylation specific-high resolution melting (MS-HRM) analysis was utilized to quantify the methylation degree of selected CpG sites localized in the promoter region of the PLA2R1 gene. Expression of miRNA was tested using miScript Primer Assay system.ResultsNearly complete methylation of the analyzed PLA2R1 promoter region along with PLA2R1 gene silencing was identified in MDA-MB-453 mammary cancer cells. In MCF-7 and BT-474 mammary cancer cell lines, a higher DNA methylation degree and reduced PLA2R1 expression were found in comparison with those in normal HMEC. Synergistic effects of demethylating agent (5-aza-2′-deoxycytidine) and histone deacetylase inhibitor (trichostatin A) on PLA2R1 transcription in MDA-MB-453 cells confirmed the importance of DNA methylation and histone modification in the regulation of the PLA2R1 gene expression in mammary cells. Furthermore, significant positive correlation between the expression of DNMT1 and PLA2R1 gene methylation and negative correlation between the cellular levels of hsa-mir-141, −181b, and -181d-1 and the expression of PLA2R1 were identified in the analyzed cells. Analysis of combined z-score of miR-23b, −154 and -302d demonstrated a strong and significant positive correlation with PLA2R1 expression.ConclusionsOur data indicate that (i) PLA2R1 expression in breast cancer cells is controlled by DNA methylation and histone modifications, (ii) hypermethylation of the PLA2R1 promoter region is associated with up-regulation of DNMT1, and (iii) hsa-miR-23b, −154, and −302d, as well as hsa-miR-141, −181b, and −181d-1 are potential candidates for post-transcriptional regulation of PLA2R1 expression in mammary cancer cells.

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“…It is clear that epigenetic states can be disrupted by environmental factors and the importance of epigenetic alterations in human diseases is becoming increasingly evident [1][2][3]. Newer classes of drugs are being developed to regulate epigenetic mechanisms and counteract disease states [4]. DNA methylation is a well-studied epigenetic modification that has been associated with several human diseases including cancer, cardiovascular disease, rheumatoid arthritis and brain disease [5][6][7][8].…”

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confidence: 99%

Evaluation of Post‐Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation

Sjöholm

Ransome

Ekström

et al. 2017

Basic Clin Pharma Tox

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The number of epigenetic studies on brain functions and diseases are dramatically increasing, but little is known about the impact of post-mortem intervals and post-sampling effects on DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Here, we examined post-mortem-induced changes in global brain 5mC and 5hmC levels at post-mortem intervals up to 540 min., and studied effects of tissue heat stabilization, using LUMA and ELISA. The global 5mC and 5hmC levels were generally higher in the cerebellum of adult rats than neonates. When measured by ELISA, the global 5mC content in adults, but not neonates, decreased with the post-mortem interval reaching a significantly lower level in cerebellum tissue at the post-mortem interval 540 min. (2.9 ± 0.7%; mean ± S.E.M.) compared to control (3.7 ± 0.6%). The global 5hmC levels increased with post-mortem interval reaching a significantly higher level at 540 min. (0.29 ± 0.06%) compared to control (0.19 ± 0.03%). This suggests that the post-mortem interval may confound 5mC and 5hmC analysis in human brain tissues as the post-mortem handling could vary substantially. The reactive oxygen species (ROS) level in cerebellum also increased over time, in particular in adults, and may be part of the mechanism that causes the observed post-mortem changes in 5mC and 5hmC. The global 5mC and 5hmC states were unaffected by heat stabilization, allowing analysis of tissues that are stabilized to preserve more labile analytes. Further studies in human samples are needed to confirm post-mortem effects on DNA methylation/hydroxymethylation and elucidate details of the underlying mechanisms.

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Epigenetics and pharmacology

Cited by 21 publications

References 17 publications

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

Fingerprinting of neurotoxic compounds using a mouse embryonic stem cell dual luminescence reporter assay

Epigenetic control of phospholipase A2 receptor expression in mammary cancer cells

Evaluation of Post‐Mortem Effects on Global Brain DNA Methylation and Hydroxymethylation

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