UHRF1 targets DNMT1 for DNA methylation through cooperative binding of hemi-methylated DNA and methylated H3K9.

Epigenetic inheritance of DNA methylation in mammals requires a multifunctional protein UHRF1, which is believed to recruit DNMT1 to DNA replication forks through a unique hemi-methylated CpG-binding activity. Here we demonstrate that the UHRF1 mutants deficient in binding either hemi-methylated CpG or H3K9me2/3, but not both, are able to associate with pericentric heterochromatin, recruit Dnmt1 and partially rescue DNA methylation defects in mouse Uhrf1 null ES cells. Furthermore, we present evidence that the flip out of the methylated cytosine induced by UHRF1 binding is unlikely essential for subsequent DNA methylation by DNMT1. Together, our study demonstrates that UHRF1 can target DNMT1 for DNA maintenance methylation through binding either H3K9me2/3 or hemi-methylated CpG, and that the presence of both binding activities ensures high fidelity DNA maintenance methylation. In addition, our study indicates that UHRF1 mediates cross-talk between H3K9 methylation and DNA methylation at the level of DNA methylation maintenance.