Epigenetic inheritance through self-recruitment of the polycomb repressive complex 2

Abstract

Maintenance of gene expression through epigenetic mechanisms such as DNA- and histone-methylation is essential for preserving cellular identity and function. Multiplication of eukaryotic cells requires that the DNA content of the cell is duplicated through replication, which is coupled to incorporation of de novo synthesized core histones into nucleosomal structures. One of the challenging questions in biology is to explain how the organism ensures that regulatory epigenetic marks, once established, are transferred from one cell generation to the next. Based on studies in our laboratory, we have recently proposed a model for how the methylated lysine 27 of histone H3 (H3K27) can be stably transmitted through the cell division cycle. We found that the Polycomb Repressive Complex 2 (PRC2), which is responsible for di- and trimethylation of H3K27 (H3K27me2/me3), binds to its own site of methylation. Moreover, our results suggested that maintenance of transcriptional repression by PRC2 requires the binding of the PRC2 complex to H3K27me3/me2. Based on these two key observations we propose that PRC2 is able to copy the mark from an old parental H3 molecule to a newly synthesized H3 molecule as DNA replication proceeds. In addition, our results support a model for how the H3K27me3 mark could be preserved in the interphase of the cell cycle, where other events such as histone exchange and demethylation could counteract PRC2 function. Here we discuss the implications of our results in further detail.