Can methylation of a promoter induce gene expression in some rare cases?

Question

Can methylation of a promoter induce gene expression in some rare cases?

I've read somewhere that methylation of an intron can induce gene expression (eg. Igf2). How is that even possible?

Thank you in advance!

Answer 1

There is nothing intrinsic to DNA methylation itself that requires it to repress transcription. Simply, it affects sequence recognition by proteins. CpG methylation can prevent transcription factor binding and/or recruit proteins that inhibit transcription, either competitively or through chromatin condensation. This is why it's generally associated with transcriptional repression.

I have found some articles which describe methylation in intergenic regions and introns activating transcription but, since you're asking specifically about promoters, I'll limit the examples to methylation in the 5' flanking region. Please note that I'm grossly oversimplifying these articles, you should actually read them to get the full picture.

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Bahar HK, Vana T, Walker MD. 2014. Paradoxical role of DNA methylation in activation of FoxA2 gene expression during endoderm development. J Biol Chem 289(34):23882-23892

This study reports that, during development, high levels of methylation of a CpG island in the FoxA2 promoter is present in expressing tissues and absent in non-expressing tissues. Their hypothesis is that CpG methylation prevents binding of a protein that represses transcription by condensing chromatin through histone modifications.

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Hantusch B, Kalt R, Krieger S, Puri C, Kerjaschki D. 2007. Sp1/Sp3 and DNA-methylation contribute to basal transcriptional activation of human podoplanin in MG63 versus Saos-2 osteoblastic cells. BMC Mol Bio 8(20)

Here, PDPN expression was associated with CpG methylation. They hypothesize that methylation could affect chromatin state or recruit, what they term, a methylation dependent factor, which activates transcription.

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Niesen MI, Osborne AR, Yang H, Rastogi S, Chellappan S, Cheng JQ, Boss JM, Blanck G. 2005. Activation of a methylated promoter mediated by a sequence-specific DNA-binding protein, RFX. J Biol Chem 280(47):38914-38922

This study describes a DNA binding protein (RFX) that can recognize and activate the methylated promoter of MHC. They suggest that RFX can competitively inhibit binding of methyl-DNA binding domain proteins that condense chromatin.