8-OxoG in GC-rich Sp1 binding sites enhances gene transcription in adipose tissue of juvenile mice

Jong Woo Park,Tae Min Kim,Joonghoon Park,Young In Han,Jaeku Kang,Su Cheong Yeom,Sung Woo Kim

doi:10.1038/s41598-019-52139-z

Jong Woo Park, Tae Min Kim + Show 5 more

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https://doi.org/10.1038/s41598-019-52139-z

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The oxidation of guanine to 8-oxoguanine (8-oxoG) is the most common type of oxidative DNA lesion. There is a growing body of evidence indicating that 8-oxoG is not only pre-mutagenic, but also plays an essential role in modulating gene expression along with its cognate repair proteins. In this study, we investigated the relationship between 8-oxoG formed under intrinsic oxidative stress conditions and gene expression in adipose and lung tissues of juvenile mice. We observed that transcriptional activity and the number of active genes were significantly correlated with the distribution of 8-oxoG in gene promoter regions, as determined by reverse-phase liquid chromatography/mass spectrometry (RP-LC/MS), and 8-oxoG and RNA sequencing. Gene regulation by 8-oxoG was not associated with the degree of 8-oxoG formation. Instead, genes with GC-rich transcription factor binding sites in their promoters became more active with increasing 8-oxoG abundance as also demonstrated by specificity protein 1 (Sp1)- and estrogen response element (ERE)-luciferase assays in human embryonic kidney (HEK293T) cells. These results indicate that the occurrence of 8-oxoG in GC-rich Sp1 binding sites is important for gene regulation during adipose tissue development.

Highlights

The oxidation of guanine to 8-oxoguanine (8-oxoG) is the most common type of oxidative DNA lesion
The level of 8-oxoG was lower in lung tissues than in liver or adipose tissues (p < 0.01). These results demonstrate that 8-oxoG is present at a low but significantly different level in genomic DNA of adipose and lung tissues of juvenile mice; these tissues were subjected to further analyses
Only two of the off genes had GC-rich transcription factor binding motifs, which was significantly lower frequency than active genes (p < 0.0154). These results indicate that genes essential for the development and function of adipose tissue would be upregulated by 8-oxoG formation, and adipose tissue-specific genes have GC-rich promoters being regulated by the epigenetic function of 8-oxoGs

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The oxidation of guanine to 8-oxoguanine (8-oxoG) is the most common type of oxidative DNA lesion. Genes with GC-rich transcription factor binding sites in their promoters became more active with increasing 8-oxoG abundance as demonstrated by specificity protein 1 (Sp1)- and estrogen response element (ERE)-luciferase assays in human embryonic kidney (HEK293T) cells. These results indicate that the occurrence of 8-oxoG in GC-rich Sp1 binding sites is important for gene regulation during adipose tissue development. 8-oxoG DNA glycosylase 1 (OGG1) is known as a bi-functional glycosylase coupled with lyase activity[6]; recent findings indicate that OGG1 is a primary DNA glycosylase to hydrolyze the 8-oxoG from the lesion, generating an abasic site[7,8]. Genome-wide profiling of 8-oxoG in rat renal tissues revealed that the lesion is preferentially located in the gene deserts, and that the gene expression is not related with the distribution of 8-oxoGs13

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