Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity Journal Article

Authors: Zhao, X.; Jankovic, V.; Gural, A.; Huang, G.; Pardanani, A.; Menendez, S.; Zhang, J.; Dunne, R.; Xiao, A.; Erdjument-Bromage, H.; Allis, C. D.; Tempst, P.; Nimer, S. D.
Article Title: Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity
Abstract: RUNX1/AML1 is required for the development of definitive hematopoiesis, and its activity is altered by mutations, deletions, and chromosome translocations in human acute leukemia. RUNX1 function can be regulated by post-translational modifications and protein-protein interactions. We show that RUNX1 is arginine-methylated in vivo by the arginine methyltransferase PRMT1, and that PRMT1 serves as a transcriptional coactivator for RUNX1 function. Using mass spectrometry, and a methyl-arginine-specific antibody, we identified two arginine residues (R206 and R210) within the region of RUNX1 that interact with the corepressor SIN3A and are methylated by PRMT1. PRMT1- dependent methylation of RUNX1 at these arginine residues abrogates its association with SIN3A, whereas shRNA against PRMT1 (or use of a methyltransferase inhibitor) enhances this association. We find arginine-methylated RUNX1 on the promoters of two bona fide RUNX1 target genes, CD41 and PU.1 and show that shRNA against PRMT1 or RUNX1 down-regulates their expression. These arginine methylation sites and the dynamic regulation of corepressor binding are lost in the leukemia-associated RUNX1-ETO fusion protein, which likely contributes to its dominant inhibitory activity. © 2008 by Cold Spring Harbor Laboratory Press.
Keywords: controlled study; unclassified drug; human cell; methylation; promoter region; mutation; dna-binding proteins; proto-oncogene proteins; protein protein interaction; rna, small interfering; transcription, genetic; cell line, tumor; transcription factors; gene expression regulation; methyltransferase; transcription regulation; hybrid protein; hematopoiesis; down regulation; trans-activators; repressor proteins; antigens, cd34; short hairpin rna; arginine; core binding factor alpha 2 subunit; protein modification; transcription factor runx1; arginine methylation; aml1 target genes; cd41; myeloid differentiation; pu.1; arginine methyltransferase prmt1; fibrinogen receptor; transcription factor sin3a; platelet membrane glycoprotein iib; protein-arginine n-methyltransferase
Journal Title: Genes and Development
Volume: 22
Issue: 5
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2008-03-01
Start Page: 640
End Page: 653
Language: English
DOI: 10.1101/gad.1632608
PUBMED: 18316480
PROVIDER: scopus
PMCID: PMC2259033
Notes: --- - "Cited By (since 1996): 28" - "Export Date: 17 November 2011" - "CODEN: GEDEE" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Jin Zhang
    23 Zhang
  2. Alexander Gural
    4 Gural
  3. Gang Huang
    12 Huang
  4. Paul J Tempst
    307 Tempst
  5. Stephen D Nimer
    345 Nimer
  6. Xinyang Zhao
    29 Zhao
  7. Richard Dunne
    2 Dunne