Molecular Cell
Volume 43, Issue 2, 22 July 2011, Pages 275-284
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Article
PHD Finger Recognition of Unmodified Histone H3R2 Links UHRF1 to Regulation of Euchromatic Gene Expression

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Summary

Histone methylation occurs on both lysine and arginine residues, and its dynamic regulation plays a critical role in chromatin biology. Here we identify the UHRF1 PHD finger (PHDUHRF1), an important regulator of DNA CpG methylation, as a histone H3 unmodified arginine 2 (H3R2) recognition modality. This conclusion is based on binding studies and cocrystal structures of PHDUHRF1 bound to histone H3 peptides, where the guanidinium group of unmodified R2 forms an extensive intermolecular hydrogen bond network, with methylation of H3R2, but not H3K4 or H3K9, disrupting complex formation. We have identified direct target genes of UHRF1 from microarray and ChIP studies. Importantly, we show that UHRF1's ability to repress its direct target gene expression is dependent on PHDUHRF1 binding to unmodified H3R2, thereby demonstrating the functional importance of this recognition event and supporting the potential for crosstalk between histone arginine methylation and UHRF1 function.

Highlights

► In vitro binding and ITC identify PHDUHRF1 domain as an unmodified histone H3R2 reader ► Crystal structure shows hydrogen bonding, electrostatics, and hydrophobic interactions ► Genome-wide analyses demonstrate a general transcriptional role for UHRF1 ► Binding unmodified H3R2 is critical for UHRF1 to regulate gene expression

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These authors contributed equally to this work