Abstract
UHRF1 is an important epigenetic regulator for maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA (hm-DNA) and trimethylation of histone H3K9 (H3K9me3), but the regulatory mechanism remains unknown. Here we show that UHRF1 adopts a closed conformation, in which a C-terminal region (Spacer) binds to the tandem Tudor domain (TTD) and inhibits H3K9me3 recognition, whereas the SET-and-RING-associated (SRA) domain binds to the plant homeodomain (PHD) and inhibits H3R2 recognition. Hm-DNA impairs the intramolecular interactions and promotes H3K9me3 recognition by TTD–PHD. The Spacer also facilitates UHRF1–DNMT1 interaction and enhances hm-DNA-binding affinity of the SRA. When TTD–PHD binds to H3K9me3, SRA-Spacer may exist in a dynamic equilibrium: either recognizes hm-DNA or recruits DNMT1 to chromatin. Our study reveals the mechanism for regulation of H3K9me3 and hm-DNA recognition by URHF1.
Highlights
UHRF1 is an important epigenetic regulator for maintenance DNA methylation
We report that UHRF1 adopts a closed conformation, in which the C-terminal Spacer binds to the tandem Tudor domain (TTD) and inhibits its recognition of H3K9me[3], whereas the SRA binds to the plant homeodomain (PHD) and inhibits its recognition of H3R2
The results are consistent with the previous observation that the interaction between TTD–PHD and the Spacer is much weaker (KD 1⁄4 10.68 mM, Fig. 3g) than that between TTD–PHD and H3K9me[3] (KD 1⁄4 0.15 mM, Fig. 1d). These results suggest that once TTD–PHD binds to H3K9me[3], UHRF1 will be locked by H3K9me[3] and the Spacer is unlikely to fold back for the intramolecular interaction
Summary
UHRF1 is an important epigenetic regulator for maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA (hm-DNA) and trimethylation of histone H3K9 (H3K9me3), but the regulatory mechanism remains unknown. How UHRF1 regulates the recognition of these two repressive epigenetic marks and recruits DNMT1 for chromatin localization remain largely unknown. We report that UHRF1 adopts a closed conformation, in which the C-terminal Spacer binds to the TTD and inhibits its recognition of H3K9me[3], whereas the SRA binds to the PHD and inhibits its recognition of H3R2 (unmethylated histone H3 at residue R2). Upon binding to hm-DNA, UHRF1 impairs the intramolecular interactions and promotes the H3K9me[3] recognition by TTD–PHD, which may further enhance its genomic localization. UHRF1 is locked in the open conformation by the association of H3K9me[3] by TTD–PHD, and SRA-Spacer either recognizes hm-DNA or recruits DNMT1 for DNA methylation. Our study reveals the mechanism for regulation of H3K9me[3] and hm-DNA recognition by UHRF1
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