PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex

Cell Rep. 2013 Dec 26;5(6):1625-38. doi: 10.1016/j.celrep.2013.11.025. Epub 2013 Dec 12.

Abstract

Defining the role of epigenetic regulators in hematopoiesis has become critically important, because recurrent mutations or aberrant expression of these genes has been identified in both myeloid and lymphoid hematological malignancies. We found that PRMT4, a type I arginine methyltransferase whose function in normal and malignant hematopoiesis is unknown, is overexpressed in acute myelogenous leukemia patient samples. Overexpression of PRMT4 blocks the myeloid differentiation of human stem/progenitor cells (HSPCs), whereas its knockdown is sufficient to induce myeloid differentiation of HSPCs. We demonstrated that PRMT4 represses the expression of miR-223 in HSPCs via the methylation of RUNX1, which triggers the assembly of a multiprotein repressor complex that includes DPF2. As part of the feedback loop, PRMT4 expression is repressed posttranscriptionally by miR-223. Depletion of PRMT4 results in differentiation of myeloid leukemia cells in vitro and their decreased proliferation in vivo. Thus, targeting PRMT4 holds potential as a novel therapy for acute myelogenous leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Core Binding Factor Alpha 2 Subunit / metabolism*
  • DNA-Binding Proteins / metabolism
  • Epigenetic Repression*
  • Hematopoiesis*
  • Humans
  • Methylation
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Myeloid Progenitor Cells / cytology
  • Myeloid Progenitor Cells / metabolism*
  • Protein Binding
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • RNA Processing, Post-Transcriptional
  • Transcription Factors

Substances

  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • DPF2 protein, human
  • MIRN223 microRNA, human
  • MicroRNAs
  • RUNX1 protein, human
  • Transcription Factors
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1

Associated data

  • GEO/GSE46056