Control of the DNA methylation system component MBD2 by protein arginine methylation.
DNA methylation is vital for proper chromatin structure and function in mammalian cells. Genetic removal of the enzymes that catalyze DNA methylation results in defective imprinting, transposon silencing, X chromosome dosage compensation, and genome stability. This epigenetic modification is interpreted by methyl-DNA binding domain (MBD) proteins. MBD proteins respond to methylated DNA by recruiting histone deacetylases (HDAC) and other transcription repression factors to the chromatin. The MBD2 protein is dispensable for animal viability, but it is implicated in the genesis of colon tumors. Here we report that the MBD2 protein is controlled by arginine methylation. We identify the protein arginine methyltransferase enzymes that catalyze this modification and show that arginine methylation inhibits the function of MBD2. Arginine methylation of MBD2 reduces MBD2-methyl-DNA complex formation, reduces MBD2-HDAC repression complex formation, and impairs the transcription repression function of MBD2 in cells. Our report provides a molecular description of a potential regulatory mechanism for an MBD protein family member. It is the first to demonstrate that protein arginine methyltransferases participate in the DNA methylation system of chromatin control.
Tan
Choon Ping
CP
Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, United Kingdom.
Nakielny
Sara
S
D000595:Amino Acid Sequence; D001120:Arginine / Q000378:metabolism*; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D020868:Gene Silencing; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000172:deficiency / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000172:deficiency / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; C115368:MBD2 protein; D050505:Mutant Proteins; D012097:Repressor Proteins; D004247:DNA; D001120:Arginine; D011496:Protein Methyltransferases; C099988:PRMT1 protein, human; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; D006655:Histone Deacetylases