DNA replication, RNAi and epigenetic inheritance.

Epigenetic marks, such as histone methylation, play a central role in chromatin structure and gene expression. During DNA replication, chromatin undergoes a wave of disruption and reassembly. Little is known about how the epigenetic marks are faithfully inherited from one generation to the next. In fission yeast, the hallmark of heterochromatin, a condensed chromatin structure, is H3K9 methylation. This conserved epigenetic mark is mediated by small interference RNAs (siRNAs) in a cell cycle-dependent manner: at S phase, heterochromatin is briefly transcribed by RNAP II and the transcripts are subsequently processed into siRNAs. These small RNAs, together with other key silencing factors, including Dos1/Raf1/Clr8/Cmc1, Dos2/Raf2/Clr7/Cmc2 and Rik1, mediate H3K9 methylation by the histone H3K9 methyltransferase Clr4. Our recent findings indicate that the ε subunit of DNA polymerase, Cdc20, associates with the Dos2-Rik1 complex and is essential for H3K9 methylation and heterochromatin function. Moreover, Cdc20 regulates siRNA generation by promoting RNAP II transcription of heterochromatin. These data suggest that DNA polymerase components may play a key role in the inheritance of histone methylation by coordinating DNA replication, RNAi and histone methylation, and explain previously observed cell cycle-regulated RNAi-dependent heterochromatin silencing. We propose a model in which, at DNA replication forks, DNA polymerase subunits mediate the recruitment of epigenetic factors required for RNAi and histone modification to heterochromatin to promote the faithful transmission of histone methylation.