PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.
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 progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5. Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.
Zhao
Quan
Q
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.|Molecular Immunology and Cancer Research Center, The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing 210093, China.
Rank
Gerhard
G
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.
Tan
Yuen T
YT
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.
Li
Haitao
H
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Moritz
Robert L
RL
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia.
Simpson
Richard J
RJ
Joint Protein Structure Laboratory, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia.
Cerruti
Loretta
L
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.
Curtis
David J
DJ
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.
Patel
Dinshaw J
DJ
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA.
Allis
C David
CD
Laboratory of Chromatin Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Cunningham
John M
JM
Department of Pediatrics and Institute of Molecular Pediatric Sciences, University of Chicago, 5839 South Maryland Avenue, Chicago, Illinois 60637, USA.
Jane
Stephen M
SM
Rotary Bone Marrow Research Laboratories, Melbourne Health Research Directorate, c/o Royal Melbourne Hospital Post Office, Grattan Street, Parkville, VIC 3050, Australia.|Department of Medicine, University of Melbourne, Grattan Street, Parkville, VIC 3050, Australia.
D001120:Arginine / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015672:Erythroid Precursor Cells / Q000737:chemistry; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011496:Protein Methyltransferases / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases
C000717967:DNMT3A protein, human; D006657:Histones; D001120:Arginine; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A