Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus
Figure 8
Model summarizing epigenetic control at the ICR of Rasgrf1.
The maternal allele (top) recruits YY1, PRC2 components, and possibly CTCF early during development or gametogenesis. H3K27 and H3K9 are both methylated (mK27 and mK9 respectively) in the vicinity of the core DMD (grey box), with optimal methylation depending upon the tandem repeats (rightward pointing black triangles, which constitute the methylation programmer). Once placed, H3K27me3 can exclude DNA methylation. On the paternal allele (bottom), the methylation programmer is active in the germline where it directs DNA methylation to the DMD [2] by a process optimized by SUV39H1 and SUV39H2 directed H3K9 methylation, and in the pre-implantation embryo where it maintains it [3]. Once established in the germline, DNA methylation on the core DMD can expand to surrounding sequences, and exclude subsequent H3K27me3 during somatic development. In the neonatal brain, where Rasgrf1 shows imprinted expression, recruitment of CTCF to the maternal allele allows the enhancer blocking activity of the DMD to silence the maternal allele by restricting interactions between a putative upstream enhancer (E) and the downstream promoter (P), while exclusion of CTCF by methylated DNA at the paternal allele allows expression [4].