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Role of multiple pericentromeric repeats on heterochromatin assembly

Although the length and constituting sequences for pericentromeric repeats are highly variable across eukaryotes, the presence of multiple pericentromeric repeats is one of the conserved features of the eukaryotic chromosomes. Pericentromeric heterochromatin is often misregulated in human diseases, with the expansion of pericentromeric repeats in human solid cancers. In this article, we have developed a mathematical model of the RNAi-dependent methylation of H3K9 in the pericentromeric region of fission yeast. Our model, which takes copy number as an explicit parameter, predicts that the pericentromere is silenced only if there are many copies of repeats. It becomes bistable or desilenced if the copy number of repeats is reduced. This suggests that the copy number of pericentromeric repeats alone can determine the fate of heterochromatin silencing in fission yeast. Through sensitivity analysis, we identified parameters that favor bistability and desilencing. Stochastic simulation shows that faster cell division favors the desilenced state whereas cellular noise favors the silenced state. These results show the unexpected role of pericentromeric repeat copy number in gene silencing and elucidate how the copy number of silenced genomic regions may impact genome stability. Significance Statement Pericentromeric repeats vary in length and sequences, but their presence is a conserved feature of eukaryotes. This suggests that the repetitive nature of pericentromeric sequences is an evolutionarily conserved feature of centromeres, which is under selective pressure. Here we developed a quantitative model for gene silencing at the fission yeast pericentromeric repeats. Our model is one of the first models which incorporate the copy number of pericentromeric repeats and predicts that the number of repeats can solely govern the dynamics of pericentromeric gene silencing. Our results suggest that the repeat copy number is a dynamic parameter for gene silencing, and copy-number-dependent silencing is an effective machinery to repress the repetitive part of the genome.