Augmented oxidative stress increases 8-oxoguanine preferentially in the transcriptionally active genomic regions

Abstract

8-Oxoguanine (8-oxoG) is the most common DNA base modification in the mammalian genome, associated with oxidative stress. Here we analysed the alterations in the distribution of 8-oxoG across the entire murine genome, before and after an elevation of oxidative stress by the use of ferric nitrilotriacetate (Fe-NTA) as an oxidative stress inducer in the renal proximal tubules. We isolated DNA fragments containing 8-oxoGs with immunoprecipitation from the murine genome, and amplified them by PCR for a distribution analysis with microarray-based comparative genomic hybridisation. The distribution profiles revealed that frequencies of 8-oxoG fluctuated with a cycle of 1–10 Mb along the chromosomes and the amplitude of the fluctuation was reduced after Fe-NTA administration. The distributions of 8-oxoG along the entire genome in the control and oxidatively stressed conditions were negatively correlated with that of gene density but positively correlated with that of Lamin B1 interaction, which corresponds to lamina-associated domains. These results on the murine genome were consistent with those on the rat genome we previously reported. We further discovered a negative correlation between the distributions of 8-oxoG and transcriptional activity along the genome. Finally, a comparison of the distributions before and after Fe-NTA administration suggested that 8-oxoGs are generated in response to the augmented oxidative stress preferentially in the transcriptionally active genomic regions, where 8-oxoGs have been less accumulated in the control condition.

Keywords:

• 8-oxoguanine
• oxygenomics
• array-based comparative genome hybridisation
• transcription
• lamina-associated domain

Disclosure statement

The authors have no conflicts of interests to disclose.

Additional information

Funding

This work was supported, in part, by JST CREST (Grant Number JPMJCR19H4), JSPS Kakenhi (Grant Number JP17H04064 and JP19H05462) and Private University Research Branding Project to ST, and by JSPS Kakenhi (Grant Number JP20K07588) to SA.