Loss of Dicer, an enzyme critical for microRNA biogenesis, results in lethality 
due to a block in mouse embryonic stem cell (mES) differentiation. Using 
ChIP-Seq we found increased H3K9me2 at over 900 CpG islands in the Dicer(-/-)ES 
epigenome. Gene ontology analysis revealed that promoters of chromatin 
regulators to be among the most impacted by increased CpG island H3K9me2 in ES 
(Dicer(-/-)). We therefore, extended the study to include H3K4me3 and H3K27me3 
marks for selected genes. We found that the ES (Dicer(-/-)) mutant epigenome was 
characterized by a shift in the overall balance between transcriptionally 
favorable (H3K4me3) and unfavorable (H3K27me3) marks at key genes regulating ES 
cell differentiation. Pluripotency genes Oct4, Sox2 and Nanog were not impacted 
in relation to patterns of H3K27me3 and H3K4me3 and showed no changes in the 
rates of transcript down-regulation in response to RA. The most striking changes 
were observed in regards to genes regulating differentiation and the transition 
from self-renewal to differentiation. An increase in H3K4me3 at the promoter of 
Lin28b was associated with the down-regulation of this gene at a lower rate in 
Dicer(-/-)ES as compared to wild type ES. An increase in H3K27me3 in the 
promoters of differentiation genes Hoxa1 and Cdx2 in Dicer(-/-)ES cells was 
coincident with an inability to up-regulate these genes at the same rate as ES 
upon retinoic acid (RA)-induced differentiation. We found that siRNAs Ezh2 and 
post-transcriptional silencing of Ezh2 by let-7 g rescued this effect suggesting 
that Ezh2 up-regulation is in part responsible for increased H3K27me3 and 
decreased rates of up-regulation of differentiation genes in Dicer(-/-)ES.