Interaction of Hereditary and Epigenetic Mechanisms in the Regulation of Gene Expression

Roman, Thaler; Aumüller, Eva; Berner, Carolin; Haslberger, Alexander G.

doi:10.1002/9783527628384.ch4

Cited by 6 publications

(5 citation statements)

References 80 publications

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“…13–15 DNA methylation is critical for normal cellular development because of its role in regulating gene transcription, maintaining transposon inactivation, X-chromosome inactivation, and genomic imprinting. DNA methylation is mediated by the family of DNA methyltransferases (DNMTs) that catalyze the transfer of a methyl group from S-adenosyl methionine (SAM) to cytosine of DNA.…”

Section: Introductionmentioning

confidence: 99%

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression

Wirbisky-Hershberger

Sánchez

Horzmann

et al. 2017

Food and Chemical Toxicology

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Atrazine, a herbicide used on agricultural crops is widely applied in the Midwestern United States as well as other areas of the globe. Atrazine frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. Previous studies have reported morphological, hormonal, and molecular alterations due to developmental and adulthood atrazine exposure; however, studies examining epigenetic alterations are limited. In this study, the effects of atrazine exposure on DNA methyltransferase (DNMT) activity and kinetics were evaluated. Global DNA methylation levels and dnmt expression in zebrafish larvae exposed to 0, 3, or 30 parts per billion (ppb) atrazine throughout embryogenesis was then assessed. Results indicate that atrazine significantly decreased the activity of maintenance DNMTs and that the inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. Furthermore, results show that an embryonic atrazine exposure decreases global methylation levels and the expression of dnmt4 and dnmt5. These findings indicate that atrazine exposure can decrease the expression and activity of DNMTs, leading to decreased DNA methylation levels.

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Section: Introductionmentioning

confidence: 99%

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression

Wirbisky-Hershberger

Sánchez

Horzmann

et al. 2017

Food and Chemical Toxicology

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“…48 DNA methylation frequently occurs at CpG islands, which usually have a GC content percentage of more than 50% and a CpG ratio of at least 60%. [49][50][51] A recent study reported that the suppression of Nrf2 expression in the lung tissue of COPD patients was caused by CpG hypermethylation in the promoter. 52 In the current study, the first two CpG sites of the Nrf2 promoter were observed to be specifically hypermethylated in peripheral lung tissues, but only the first CpG site was hypermethylated in cultures of primary epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Hypermethylation of the Nrf2 Promoter Induces Ferroptosis by Inhibiting the Nrf2-GPX4 Axis in COPD

Zhang¹,

Chen²,

Liu³

et al. 2021

COPD

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Background Nuclear factor E2-related factor 2 (Nrf2) is involved in oxidative stress and lung inflammation and regulates the etiology of chronic obstructive pulmonary disease (COPD). Ferroptosis is characterized by the accumulation of lipid reactive oxygen species (ROS) via ferrous ion-dependent Fenton reactions and is involved in COPD. However, the role of Nrf2 in ferroptosis and its epigenetic regulation in the pathogenesis of COPD remain unclear. Methods Ferroptosis was detected by 4-HNE, MDA, C11BODIPY, DCFH-DA, Peals’ staining and CCK-8 assays. qPCR and Western blotting were performed to examine the Nrf2 levels in peripheral lung tissues, primary epithelial cells collected from patients with COPD and subjects with normal pulmonary function (never-smoker [control-NS]; smoker [control-S]), and cigarette smoke extract (CSE)-treated human bronchial epithelial (HBE) cells. ELISA was used to quantify IL-8 and IL-1β levels. Methylation of the Nrf2 promoter was analyzed by bisulfite sequencing and pyrosequencing. Results Ferroptosis was involved in COPD and glutathione peroxidase 4 (GPX4) expression was downregulated in the COPD group. Reactive oxygen species (ROS), lipid peroxides and MDA were increased, but GPX4 and SOD were exhausted in CSE-treated HBE cells. The production of IL-1β and IL-8 was promoted in HBE cells in response to CSE but could be reversed by the ferroptosis inhibitor fer-1. The Nrf2 level was significantly decreased in the COPD group compared with the control-S and control-NS groups. Increased Nrf2 expression enhanced GPX4 and SOD levels and inhibited ferroptosis and proinflammatory cytokines in the supernatant. Inhibition of GPX4 reversed the effect of Nrf2 overexpression and promoted ferroptosis. Two specific CpG sites within the Nrf2 promoter were hypermethylated in the COPD group. Similarly, CSE-treated HBE cells exhibited hypermethylation of the Nrf2 gene. Conclusion Nrf2 expression was downregulated in the lungs of COPD patients due to hypermethylation of the Nrf2 promoter, inhibiting Nrf2/GPX4 and ferroptosis, which is related to the initiation and progression of COPD. Targeting Nrf2/GPX4 may inhibit ferroptosis, which could provide strategies to delay or treat COPD.

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“…Epigentic regulatory mechanism involves various post-translational covalent modifications in the histone structure that includes acetylation, deacetylation, phosphorylation, methylation ubiquitination, sumoylation (9,10). Among these acetylation and phosphorylation are flexible, reversible and unstable while methylation is concerned with long term modifications (11).…”

Section: Chromatin Modificationsmentioning

confidence: 99%

“…Non-coding RNA (ncRNA) are the ones originated from the transcription of intergenic regions of DNA (12) and do not translate into proteins (13). These ncRNA are involved in post transcriptional regulation of expression of mRNA by binding to the untranslated portion of mRNA resulting in mRNA cleavage and ultimately affects protein synthesis and regulation of gene expression (11). These ncRNAs regulate epigenetic gene expression by controlling the process of transcription through polycomb complexes that modify chromatin structure, down regulation of DNA methylation as well as affecting post transcriptional process such as splicing, translation etc.…”

Section: Rna Mediated Regulationmentioning

confidence: 99%

DNA Methylation: Bridging life’s experience and genetics within forensic scenario

Rana¹,

Ahmed²,

Kushwaha³

2023

GSC Biol. Pharm. Sci.

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DNA serving as the “blueprints of life” is a complex found in all biological cells carrying the genetic instructions for development and functioning of the organism. Inheritance of unique combination of genetic polymorphism results in DNA profile. In past few decades, the field of forensic genetics has witnessed several advancements from the radio-labelled DNA probes to the Short Tandem Repeats (STR) and Single Nucleotide Polymorphism (SNP) that have fostered the emergence of biological materials as most reliable evidences at a crime scene for the purpose of human identification but then, are inadequate in distinguishing monozygotic twins. Also, these techniques are of unavailing in providing informations such as tissue-specificity of the DNA source, phenotypic identification, and age estimation. Epigenetics, particularly DNA methylation is evolving as a promising technique to overcome such drawbacks of conventional profiling techniques.

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Interaction of Hereditary and Epigenetic Mechanisms in the Regulation of Gene Expression

Cited by 6 publications

References 80 publications

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression

Hypermethylation of the Nrf2 Promoter Induces Ferroptosis by Inhibiting the Nrf2-GPX4 Axis in COPD

DNA Methylation: Bridging life’s experience and genetics within forensic scenario

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