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Background  The activity of transposable elements can be regulated by different means. DNA CpG methylation is known to decrease or inhibit transpositional activity of diverse transposons. However, very surprisingly, it was previously shown that CpG methylation of the  Sleeping Beauty  ( SB ) transposon significantly enhanced transposition in mouse embryonic stem cells.    Results  In order to investigate the unexpected response of  SB  transposition to CpG methylation, related transposons from the  Tc1 / mariner  superfamily, that is,  Tc1 ,  Himar1 ,  Hsmar1 ,  Frog Prince  ( FP ) and  Minos  were tested to see how transposition was affected by CpG methylation. A significant increase of >20-fold in transposition of  SB ,  FP  and  Minos  was seen, whereas  Tc1 ,  Himar1  and  Hsmar1  showed no difference in transposition upon CpG-methylation. The terminal inverted repeats (TIRs) of the  SB ,  FP  and  Minos  elements share a common structure, in which each TIR contains two functionally important binding sites for the transposase (termed the IR/DR structure). The group of IR/DR elements showed increased excision after CpG methylation compared to untreated transposon donor plasmids. We found that  de novo  CpG methylation is not required for transposition. A mutated  FP  donor plasmid with depleted CpG sites in both TIRs was as efficient in transposition as the wild-type transposon, indicating that CpG sites inside the TIRs are not responsible for altered binding of factors potentially modulating transposition. By using an  in vivo  one-hybrid DNA-binding assay in cultured human cells we found that CpG methylation had no appreciable effect on the affinity of  SB  transposase to its binding sites. However, chromatin immunoprecipitation indicated that CpG-methylated transposon donor plasmids are associated with a condensed chromatin structure characterized by trimethylated histone H3K9. Finally, DNA compaction by protamine was found to enhance  SB  transposition.    Conclusions  We have shown that DNA CpG methylation upregulates transposition of IR/DR elements in the  Tc1/mariner  superfamily. CpG methylation provokes the formation of a tight chromatin structure at the transposon DNA, likely aiding the formation of a catalytically active complex by facilitating synapsis of sites bound by the transposase.

Regulation of DNA transposition by CpG methylation and chromatin structure in human cells