[No authors listed]
Hypermethylation of gene promoter has been indicated for the contribution of gene silencing, and DNA demethylating drugs, such as 5-aza-2'-deoxycytidine (DAC), has been used clinically for cancer treatment. However, the reason why a proportion of genes with hypermethylated promoter exhibit high expression levels remains unclear and this drug is not much successful as expected in use. Furthermore, CpG islands (CGIs) are found to be located in not only promotors, but also in gene bodies. By RNA-seq and reduced representation bisulfite sequencing, we found the mismatch between the level of promoter methylation and gene expression. By polymerase chain reaction and luciferase reporter assay, we identified putative promoters in gene body, and proved the activities of putative promoters were affected by the methylation level of the CGI nearby. DAC can reverse the DNA hypermethylation at promoter CGIs effectively but not the CGIs in gene body. We also found that TET1 could demethylate CGIs both in promoter and gene body. Furthermore, we revealed a novel mechanism that H3K36me3 could affect the activity of putative promoter, and 5hmC recruited MeCP2 and CREB1 as a coactivator to SETD2 promoter, to enhance its gene expression and result in increased H3K36me3 in gene body. Our results concluded that putative promoters existed in the gene bodies, and TET1 could influence the transcriptional activity of putative promoters by intragenic demethylation.
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