A cross-omics approach to investigate temporal gene expression regulation by 5-hydroxymethylcytosine via TBH-derived oxidative stress showed involvement of different regulatory kinases
| Autor: | Jos C. S. Kleinjans, Sandra M.H. Claessen, Simone G. J. van Breda, Lize Deferme, Jarno E J Wolters, Jacob J. Briedé, Twan van den Beucken, Richard Wagner |
|---|---|
| Přispěvatelé: | RS: GROW - R1 - Prevention, Toxicogenomics, Promovendi ODB |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
TET PROTEINS Serine-threonine kinases Toxicology 03 medical and health sciences chemistry.chemical_compound Liver Neoplasms Experimental 0302 clinical medicine tert-Butyl hydroperoxide tert-Butylhydroperoxide 5-Hydroxymethylcytosine HEPATOCELLULAR-CARCINOMA Gene expression Animals Humans Gene Regulatory Networks HepG2 cells LIVER CARCINOGENESIS MAPK14 Demethylation Regulation of gene expression Kinase METHYLATION Genomics Hep G2 Cells General Medicine Methylation Microarray Analysis CANCER Cell biology Oxidative Stress 030104 developmental biology Gene Expression Regulation chemistry DNA-DAMAGE 030220 oncology & carcinogenesis DNA methylation Metabolome 5-Methylcytosine Differentially expressed genes SURVIVAL RNA EMBRYONIC STEM-CELLS Protein Kinases DETOXIFYING ENZYMES |
| Zdroj: | Toxicology in Vitro, 48, 318-328. Elsevier Science |
| ISSN: | 0887-2333 |
| Popis: | Regulation of DNA methylation plays a crucial role in biological processes and carcinogenesis. The formation of 5-hydroxymethylcytosine (5hmC) by oxidation of 5-methylcytosine (5mC) has been proposed as an intermediate of active demethylation. However, whether and how active demethylation is regulated by oxidative stress-related processes is not well understood. Here we investigated whether free oxygen radicals are capable of directly forming 5hmC and how this enhanced whole genome gene expression. We applied LC-MS/MS technology for the analysis of 5mC, 5hmC, 5-formylcytosine (5fC) and 5-hydroxymethyluracyl (5hmU) in HepG2 cells exposed to hydroxyl- and methyl radicals, formed by tert-butyl hydroperoxide (TBH) at multiple time points. We observed that TBH is able to induce a significant increase in 5hmC. A detailed evaluation of the hydroxymethylome using a combination of 5hmC-immunoprecipitation and microarrays resulted in the identification of highly dynamic modifications that appear to increase during prolonged oxidant exposure. Analyses of temporal gene expression changes in combination with network analysis revealed different subnetworks containing differentially expressed genes (DEGs) with differentially hydroxyl-methylated regions (DhMRs) in different regulatory kinases enriched with serine-threonine kinases. These serine-threonine kinases compromises MAPK14, RPSK6KA1, RIPK1, and PLK3 and were all previously identified as key-regulators in hepatocarcinogenesis and subject of study for chemotherapeutic interventions. |
| Databáze: | OpenAIRE |
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