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PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.

http://www.ncbi.nlm.nih.gov/pubmed/19234465

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.

Pubmed ID: 19234465 RIS Download

Mesh terms: Arginine | DNA (Cytosine-5-)-Methyltransferase | DNA Methylation | Erythroid Precursor Cells | Gene Knockdown Techniques | Gene Silencing | Histones | Humans | Models, Biological | Protein Binding | Protein Interaction Domains and Motifs | Protein Methyltransferases | Protein-Arginine N-Methyltransferases

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL53749-03
  • Agency: NCI NIH HHS, Id: P30 CA008748
  • Agency: NCI NIH HHS, Id: P30 CA021765
  • Agency: NIGMS NIH HHS, Id: R01 GM040922
  • Agency: NHLBI NIH HHS, Id: R01 HL69232-01

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