Last week PLoS Genetics ran a great paper from Anders Lindroth and colleagues illustrating a mutually exclusive relationship between DNA Methylation and methylation of H3K27 in the a differentially methylation domain (DMD) of an imprinting control region (ICR). Now before we drop any more epi-breviations….
The area of focus in the study was a 12 kb region of Rasgrf1, an interesting locus where the paternal allele is active despite exhibiting DNA methylation and other repressive marks, while the maternal allele is silent, lacks DNA methylation, but shows other repressive marks.
Possible mechanisms for this mutual exclusivity that were proposed included:
- Methylation modifications were imposed in different locations in the nucleus
- The required factors for introducing methylation to DNA, or H3K27 dock in the same location which allows for one modification to be introduced
Both of these mechanisms seem plausible but instead, the team showed that:
- DNA Methylation and H3K27 methylation were not only mutually exclusive, but antagonistic as well.
They showed this in not just one, or two approaches, but FIVE different ways:
1. Mouse embryonic fibroblasts (MEFs) taken from mice lacking DNA methylation on the paternal DMD inappropriately accumulated H3K27me3 on the paternal allele
2. MEFs treated with 5-azacytidine led to high levels of H3K27me3 marks
3. MEFs taken from mice with a maternally transmitted Rasgrf1 ICR lacking DNA methylation exhibited H3K27me3 on the transgenic DMD, whereas H3K27me3 was excluded by manipulations that placed DNA methylation in inappropriate spots on the transgene
4. Mutating the Suz12 component of PRC2 (required for the EZH2 H3K27 methyltransferase in PRC2) impeded normal placement of H3K27me3 AND enabled the maternal allele to inappropriately acquire DNA methylation
5. Mutating the Yy1 gene (required for for recruiting PRC2 to DNA and, like Suz12, is needed for proper H3K27me3 placement) allowed the maternal allele to acquire DNA methylation.
For more details check out the Open Access paper at:
Lindroth AM, Park YJ, McLean CM, Dokshin GA, Persson JM, et al. (2008) Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus. PLoS Genetics, August 2008