Herzig, A.; Stephenson, H. N.; Streeck, R.

The Polycomb system maintains cell fate decisions by establishing silenced chromatin at developmental regulators. This is mediated by histone H3 lysine 27 trimethylation (H3K27me3) deposited in highly modified chromatin domains by Polycomb repressive complex 2 (PRC2). Increasing evidence suggests that the Polycomb system has functions beyond developmental regulation but the underlying mechanisms remained unclear. Here, we show that large regions of the genome are moderately modified by H3K27me3 and transcriptionally repressed through PRC2. In contrast to genes in silenced chromatin, moderately modified genes remain inducible by physiological stimuli and the repressive function of PRC2 is balanced by activating inputs from the Trithorax system. This demonstrates a pervasive function of the Polycomb system in dynamically regulating homeostatic expression and inducibility of genes in differentiated cells.