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  current news   Press   selected story    
     
  10th February 2012  
 

Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance

 
 




Authors
Migliori V1,2, Müller J1, Phalke S1, Low D1,3, Bezzi M1,2, Mok WC1, Sahu SK1, Gunaratne J1, Capasso P4, Bassi C5,7, Cecatiello V5, De Marco A4, Blackstock W1, Kuznetsov V3, Amati B5,6, Mapelli M5, Guccione E1,2.

1 - Institute of Molecular and Cell Biology, Singapore.
2 - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3 - Bioinformatics Institute, Singapore.
4 - Cogentech, Protein Chemistry Unit, Milan, Italy.
5 - Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
6 - Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
7 - Current address: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Published in Nature Structural & Molecular Biology 2012 Jan 8;19(2):136-44

Abstract
The asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a) acts as a repressive mark that antagonizes trimethylation of H3 lysine 4. Here, we report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. Profiling of H3-tail interactors by SILAC MS revealed that H3R2me2s excludes binding of RBBP7, a central component of co-repressor complexes Sin3a, NURD and PRC2. Conversely, H3R2me2s enhances binding of WDR5, a common component of the coactivator complexes MLL, SET1A, SET1B, NLS1 and ATAC. The interaction of histone H3 with WDR5 distinguishes H3R2me2s from H3R2me2a, which impedes the recruitment of WDR5 to chromatin. The crystallographic structure of WDR5 and the H3R2me2s peptide elucidates the molecular determinants of this high affinity interaction. Our findings identify H3R2me2s as a previously unknown mark that keeps genes poised in euchromatin for transcriptional activation upon cell-cycle withdrawal and differentiation in human cells.

 
 

 
 


Figure Legend : Crystal structure of WDR5 bound to the N terminus of histone H3 symmetrically dimethylated on arginine 2. (a,b) Cartoon representation of WDR5 in complex with (a) R2me2s- and (b) unmodified (PDB 2H13 (ref. 39)) histone H3 peptides. Histone H3 peptides, in yellow ball-and-stick representation, bind the narrower top surface of the WDR5 β-propeller and insert the Arg2 side chain into its central channel. (c,d) Enlarged view of the Arg2 interaction network. The hydrophobic part of the arginyl side chain is stabilized by the phenylalanine clamp formed by Phe133 and Phe263 (purple sticks), while the guanidinium group participates in direct and water-mediated bonding to hydrogen (dashed lines). Two hydrogen bonds to structurally conserved water molecules anchor the unmodified Arg2 to the bottom of the WDR5 channel. The dimethylated side chain displaces one of the waters and protrudes toward the Phe219 aromatic ring to make tighter hydrophobic interactions. (e) Superposition of the two structures.

For more information on Ernesto GUCCIONE’s laboratory, please click here.