Yang et al. initially set out to test the significance of a known interaction between the histone methyltransferase SUV39H1 and PC2. Using mass spectrometry and mutational analysis, they found that PC2 is dimethylated at Lys191 and that this modification is added specifically by SUV39H1 and removed by Lys-specific demethylase 4C (KDM4C). They next asked whether PC2 methylation might be relevant for cell cycle and growth control. Chromatin immunoprecipitation followed by sequencing (ChIP–seq) analysis showed that dimethylated PC2 was enriched at E2F1 target gene promoters and that serum stimulation, which triggers the activation of E2F1 target genes, increased the levels of demethylated PC2 and the recruitment of KDM4C here. Moreover, depletion of KDM4C prevented the expression of E2F1 target genes in response to serum, highlighting a requirement for PC2 demethylation. Indeed, overexpression of a mutant form of PC2 that mimics the demethylated form increased cell proliferation in HeLa cells and primary fibroblasts, whereas PC2 depletion impaired cell proliferation in response to serum.
The nucleus is organized into regions that are potentially repressive or activating for gene expression, so the authors asked whether PC2 might contribute to the relocation of genes upon the induction of growth signalling. Consistent with this, closer inspection revealed that, whereas methylated PC2 associates with markers for repressive Pc group (PcG) bodies, unmethylated PC2 localizes to the more 'activating' environment of interchromatin granules (ICGs). This was paralleled by a similar relocalization of PC2-associated E2F1 target genes to ICGs upon serum stimulation, and both required the demethylation of PC2.
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