Journal article
PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing
Quan Zhao, Gerhard Rank, Yuen T Tan, Haitao Li, Robert L Moritz, Richard J Simpson, Loretta Cerruti, David J Curtis, Dinshaw J Patel, C David Allis, John M Cunningham, Stephen M Jane
NATURE STRUCTURAL & MOLECULAR BIOLOGY | NATURE PUBLISHING GROUP | Published : 2009
DOI: 10.1038/nsmb.1568
Abstract
Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious. Using the human beta-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. In primary erythroid pro..
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Awarded by US National Institutes of Health
Awarded by The Natural Science Foundation of China
Awarded by Cancer Centre Support CORE
Awarded by NATIONAL CANCER INSTITUTE
Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
Funding Acknowledgements
We thank S. Pestka (University of Medicine and Dentistry of New Jersey) for the PRMT5 Delta plasmid, R. Gaynor (University of Texas Southwestern) for the PRMT5 plasmid and members of the Jane and Cunningham laboratories for helpful discussions. This work was supported by grants from The National Health and Medical Research Council of Australia, the US National Institutes of Health (PO1 HL53749-03 and RO1 HL69232-01) (S.M.J.), The Roche Foundation for anemia research (RoFAR) (S.M.J.), The Cooley's Anemia Foundation (Q.Z.), The Natural Science Foundation of China #30670422 (Q.Z.), Cancer Centre Support CORE Grant P30 CA 21765, the American Lebanese Syrian Associated Charities (ALSAC) and the Assisi Foundation of Memphis (J.M.C.).