Association of UHRF1 with H3K9 methylation directs the maintenance of DNA methylation

A fundamental challenge in mammalian biology has been elucidating mechanisms linking DNA methylation and histone post-translational modifications. Human UHRF1 (ubiquitin-like, PHD and RING finger containing 1) has multiple domains that bind chromatin and is implicated genetically in DNA methylation maintenance. However, molecular mechanisms underlying DNA methylation regulation by UHRF1 are poorly defined. Here we show that UHRF1 association with methylated histone H3 lysine 9 (H3K9) is required for DNA methylation maintenance. We further show that UHRF1 association with H3K9 methylation is insensitive to adjacent H3 serine 10 phosphorylation – a known mitotic ‘phospho/methyl switch.’ Importantly, we demonstrate that UHRF1 mitotic chromatin association is necessary for DNA methylation maintenance through regulation of DNMT1 stability. Collectively, our results define a novel link between H3K9 methylation and the faithful epigenetic inheritance of DNA methylation, establishing an unexpected mitotic role for UHRF1 in this process.