Genome-wide profiling of 8-oxoguanine reveals its association with spatial positioning in nucleus.
Bottom Line: 8-Oxoguanine (8-oxoG) is one of the most common DNA lesions generated by reactive oxygen species.Genome-wide mapping of 8-oxoG in normal rat kidney revealed that 8-oxoG is preferentially located at gene deserts.We did not observe differences in 8-oxoG levels between groups of genes with high and low expression, possibly because of the generally low 8-oxoG levels in genic regions compared with gene deserts.
Affiliation: Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.Show MeSH
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Mentions: There are several possible reasons for the differences in 8-oxoG levels along chromosomes. According to the CT model, gene-rich regions tend to be located towards the interior of the nucleus, whereas gene-poor regions are closer to the nuclear periphery.24 The negative correlation observed between the 8-oxoG level and gene density may reflect the spatial architecture of chromosomes in the nucleus. LADs are well-characterized structural features of chromosomes.31 Therefore, we focused on the relationship between 8-oxoG and LADs. The distribution profiles of 8-oxoG and LADs are highly similar, suggesting that 8-oxoG is preferentially formed in LADs. This can be interpreted in at least two ways. One possible explanation is that LADs occupy the outermost regions of chromosomes in the nuclear spatial architecture. These regions are more exposed to the external oxidative stresses than the centrally located parts of chromosomes and more likely to be modified (Fig. 7A). This observation is consistent with the ‘bodyguard’ hypothesis proposed by Hsu.43 The author argued that heterochromatin localized at the nuclear periphery may protect the centrally located euchromatin against mutagens and other substances that modify chromosomal DNA. Although experimental evidence that directly supports this hypothesis was not provided for a long time,34 our observation that 8-oxoG tends to co-localize with LADs is in agreement with the hypothesis. In addition, guanine is known to be susceptible to oxidation because of its low oxidation potential, leading to a speculation that the formation of 8-oxoG may protect other genomic regions from mutagenesis due to oxidative stress.44Figure 7.
Affiliation: Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.