The histone methyltransferases Set5 and Set1 have overlapping functions in gene silencing and telomere maintenance.

Genes adjacent to telomeres are subject to transcriptional repression mediated by an integrated set of chromatin modifying and remodeling factors. The telomeres of Saccharomyces cerevisiae have served as a model for dissecting the function of diverse chromatin proteins in gene silencing, and their study has revealed overlapping roles for many chromatin proteins in either promoting or antagonizing gene repression. The H3K4 methyltransferase Set1, which is commonly linked to transcriptional activation, has been implicated in telomere silencing. Set5 is an H4 K5, K8, and K12 methyltransferase that functions with Set1 to promote repression at telomeres. Here, we analyzed the combined role for Set1 and Set5 in gene expression control at native yeast telomeres. Our data reveal that Set1 and Set5 promote a Sir protein-independent mechanism of repression that may primarily rely on regulation of H4K5ac and H4K8ac at telomeric regions. Furthermore, cells lacking both Set1 and Set5 have highly correlated transcriptomes to mutants in telomere maintenance pathways and display defects in telomere stability, linking their roles in silencing to protection of telomeres. Our data therefore provide insight into and clarify potential mechanisms by which Set1 contributes to telomere silencing and shed light on the function of Set5 at telomeres.

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