Abstract
The roles of eukaryotic DNA methylation in the repression of mRNA transcription and in the formation of heterochromatin have been extensively elucidated over the past several years. However, the role of DNA methylation in transcriptional activation remains a mystery. In particular, it is not known whether the transcriptional activation of methylated DNA is promoter-specific, depends directly on sequence-specific DNA-binding proteins, or is facilitated by the methylation. Here we report that the sequence-specific DNA-binding protein, RFX, previously shown to mediate the transition from an inactive to an active chromatin structure, activates a methylated promoter. RFX is capable of mediating enhanceosome formation on a methylated promoter, thereby mediating a transition from a methylation-dependent repression of the promoter to a methylation-dependent activation of the promoter. These results indicate novel roles for DNA methylation and sequence-specific DNA-binding proteins in transcriptional activation.
Highlights
IntroductionDNA methylation of the far upstream region of the INTERLEUKIN-8 gene and methylation of the EARLY GROWTH RESPONSE-2 intron are associated with increased promoter activity [9, 10]
In several rare cases, DNA methylation has been shown to enhance transcription
We report that the sequence-specific DNA-binding protein, RFX, can mediate the transcriptional activation of a methylated major histocompatibility (MHC) gene promoter that was repressed by the methylation
Summary
DNA methylation of the far upstream region of the INTERLEUKIN-8 gene and methylation of the EARLY GROWTH RESPONSE-2 intron are associated with increased promoter activity [9, 10]. The mechanism of these effects is unknown, and no DNA-binding proteins involved in these processes have been identified. We report that the sequence-specific DNA-binding protein, RFX, can mediate the transcriptional activation of a methylated major histocompatibility (MHC) gene promoter that was repressed by the methylation. These results indicate that DNA demethylation is not necessary for promoter de-repression, i.e. for a loss of proteins that block the binding of positive transcriptional regulatory proteins; and that DNA demethylation is not necessary for promoter activation, defined as an initial promoter-protein interaction that facilitates the interaction of the promoter with positive transcriptional regulatory proteins
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