We have recently reported that the protein ZRF1 specifically binds to 
monoubiquitinated histone H2A and derepresses Polycomb target genes at the onset 
of cellular differentiation. Our results suggest that ZRF1 exerts its function 
in a two-step mechanism, by initially displacing the Polycomb-repressive complex 
1 (PRC1) from chromatin and subsequently acting together with histone 
H2A-specific deubiquitinases to facilitate transcriptional activation of its 
target genes. These findings demonstrate an ambiguity of the epigenetic 
monoubiquitin mark at histone H2A. Once considered to be a hallmark of gene 
silencing, it is now clear that this mark can also be utilized as a recruitment 
platform for proteins engaged in gene activation. Genome-wide analyses 
demonstrate that ZRF1 is recruited to typical Polycomb target genes, thereby 
putting it in a position to have an impact on differentiation and animal 
development. This molecular mechanism for ZRF1 may represent one of the first 
steps in switching silenced genes to a transcriptionally active state. We 
discuss here our recent findings in the light of progress made in understanding 
Polycomb-mediated silencing.