Abstract
Polycomb group proteins are essential epigenetic repressors. They form multiple protein complexes of which two kinds, PRC1 and PRC2, are indispensable for repression. Although much is known about their biochemical properties, how mammalian PRC1 and PRC2 are targeted to specific genes is poorly understood. Here, we establish the cyclin D2 (CCND2) oncogene as a simple model to address this question. We provide the evidence that the targeting of PRC1 to CCND2 involves a dedicated PRC1-targeting element (PTE). The PTE appears to act in concert with an adjacent cytosine-phosphate-guanine (CpG) island to arrange for the robust binding of PRC1 and PRC2 to repressed CCND2 Our findings pave the way to identify sequence-specific DNA-binding proteins implicated in the targeting of mammalian PRC1 complexes and provide novel link between polycomb repression and cancer.
Highlights
Sweden and the ¶Division of Chemical, Biological, Radioactive and Nuclear (CBRN) Security and Defence, FOI–Swedish Defence
Drosophila cells, we noted that some of the Polycomb group (PcG) target genes, when transcriptionally active, have their PREs bound by PRC1 in the absence of PRC2 and H3K27me3 [40, 48]
Analyzing previously published chromatin immunoprecipitation (ChIP)– binding profiles [55], we noticed that in the human embryonic teratocarcinoma NT2-D1 cells this region is strongly immunoprecipitated with antibodies against BMI1 and MEL18 but very weakly with antibodies against EZH2 and H3K27me3
Summary
PRC1 and PRC2 complexes usually act together to effect epigenetic repression. in experiments with cultured. H3K27me, CBX8, and SUZ12, and up-regulated upon the knockdown of PRC1 and PRC2 [56] This indicates that CCND2 is a regular PcG target gene that, when transcriptionally inactive, acquires the chromatin state characteristic of PcG repression but binds a lot of PRC1 and little PRC2 and H3K27me in cells where it is transcriptionally active. (2018) 293(37) 14342–14358 positive control ALX4 gene (Fig. 2), which is transcriptionally inactive and bound by PRC1 and PRC2 in both NT2-D1 and TIG-3 cells [55, 57, 58] These are paralleled by weak ChIP signals for H3K27me. It suggests that the putative PTE is not capable of retaining PRC2 as efficiently as activities linked to the adjacent CpG-rich region
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