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Human NEIL3 Gene Expression Regulated by Epigenetic-Like Oxidative DNA Modification.

ABSTRACT: The NEIL3 DNA repair gene is induced in cells or animal models experiencing oxidative or inflammatory stress along with oxidation of guanine (G) to 8-oxo-7,8-dihydroguanine (OG) in the genome. We hypothesize that a G-rich promoter element that is a potential G-quadruplex-forming sequence (PQS) in NEIL3 is a site for introduction of OG with epigenetic-like potential for gene regulation. Activation occurs when OG is formed in the NEIL3 PQS located near the transcription start site. Oxidative stress either introduced by TNFα or synthetically incorporated into precise locations focuses the base excision repair process to read and catalyze removal of OG via OG-glycosylase I (OGG1), yielding an abasic site (AP). Thermodynamic studies showed that AP destabilizes the duplex, enabling a structural transition of the sequence to a G-quadruplex (G4) fold that positions the AP in a loop facilitated by the NEIL3 PQS having five G runs in which the four unmodified runs adopt a stable G4. This presents AP to apurinic/apyrimidinic endonuclease 1 (APE1) that poorly cleaves the AP backbone in this context according to in vitro studies, allowing the protein to function as a trans activator of transcription. The proposal is supported by chemical studies in cellulo and in vitro. Activation of NEIL3 expression via the proposed mechanism allows cells to respond to mutagenic DNA damage removed by NEIL3 associated with oxidative or inflammatory stress. Lastly, inspection of many mammalian genomes identified conservation of the NEIL3 PQS, suggesting this sequence was favorably selected to function as a redox switch with OG as the epigenetic-like regulatory modification.

SUBMITTER: Fleming AM

PROVIDER: S-EPMC6640110 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytosine methylation, epigenetic DNA modification, is well known to regulate gene expression. Among the epigenetic modifications, 5-methylcytosine (5-mC) has been one of the extensively studied epigenetic changes responsible for regulating gene expression in animals and plants. Though a dramatic change in 5-mC content is observed at the genome level, the variation in gene expression is generally less than that it is expected. Only less is understood about the significance of 5-mC in gene regulation under P-starvation stress in plants. Using whole-genome bisulfite sequencing of a pair of rice [Pusa-44 and its near-isogenic line (NIL)-23 harboring Pup1 QTL] genotypes, we could decipher the role of Pup1 on DNA (de)methylation-mediated regulation of gene expression under P-starvation stress. We observed 13-15% of total cytosines to be methylated in the rice genome, which increased significantly under the stress. The number of differentially methylated regions (DMRs) for hypomethylation (6,068) was higher than those (5,279) for hypermethylated DMRs under the stress, particularly in root of NIL-23. Hypomethylation in CHH context caused upregulated expression of 489 genes in shoot and 382 genes in root of NIL-23 under the stress, wherein 387 genes in shoot and 240 genes in root were upregulated exclusively in NIL-23. Many of the genes for DNA methylation, a few for DNA demethylation, and RNA-directed DNA methylation were upregulated in root of NIL-23 under the stress. Methylation or demethylation of DNA in genic regions differentially affected gene expression. Correlation analysis for the distribution of DMRs and gene expression indicated the regulation of gene mainly through (de)methylation of promoter. Many of the P-responsive genes were hypomethylated or upregulated in roots of NIL-23 under the stress. Hypermethylation of gene body in CG, CHG, and CHH contexts caused up- or downregulated expression of transcription factors (TFs), P transporters, phosphoesterases, retrotransposon proteins, and other proteins. Our integrated transcriptome and methylome analyses revealed an important role of the Pup1 QTL in epigenetic regulation of the genes for transporters, TFs, phosphatases, carbohydrate metabolism, hormone-signaling, and chromatin architecture or epigenetic modifications in P-starvation tolerance. This provides insights into the molecular function of Pup1 in modulating gene expression through DNA (de)methylation, which might be useful in improving P-use efficiency or productivity of rice in P-deficient soil.

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Human NEIL3 Gene Expression Regulated by Epigenetic-Like Oxidative DNA Modification.

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