Arginine methylation provides epigenetic transcription memory for retinoid-induced differentiation in myeloid cells

Mol Cell Biol. 2005 Jul;25(13):5648-63. doi: 10.1128/MCB.25.13.5648-5663.2005.

Abstract

Cellular differentiation is governed by changes in gene expression, but at the same time, a cell's identity needs to be maintained through multiple cell divisions during maturation. In myeloid cell lines, retinoids induce gene expression and a well-characterized two-step lineage-specific differentiation. To identify mechanisms that contribute to cellular transcriptional memory, we analyzed the epigenetic changes taking place on regulatory regions of tissue transglutaminase, a gene whose expression is tightly linked to retinoid-induced differentiation. Here we report that the induction of an intermediary or "primed" state of myeloid differentiation is associated with increased H4 arginine 3 and decreased H3 lysine 4 methylation. These modifications occur before transcription and appear to prime the chromatin for subsequent hormone-regulated transcription. Moreover, inhibition of methyltransferase activity, pre-acetylation, or activation of the enzyme PAD4 attenuated retinoid-regulated gene expression, while overexpression of PRMT1, a methyltransferase, enhanced retinoid responsiveness. Taken together, our results suggest that H4 arginine 3 methylation is a bona fide positive epigenetic marker and regulator of transcriptional responsiveness as well as a signal integration mechanism during cell differentiation and, as such, may provide epigenetic memory.

Publication types

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

MeSH terms

  • Acetylation
  • Arginine / metabolism
  • Cell Differentiation / drug effects*
  • Cell Lineage
  • Chromatin / metabolism
  • DNA Methylation*
  • Epigenesis, Genetic*
  • Gene Expression Regulation / drug effects
  • Genetic Markers
  • HL-60 Cells
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Hydrolases / metabolism
  • Ionophores / pharmacology
  • Models, Biological
  • Myeloid Cells / drug effects*
  • Myeloid Cells / metabolism
  • Promoter Regions, Genetic
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases
  • Protein-Arginine N-Methyltransferases / metabolism
  • Retinoids / pharmacology*
  • Transcription, Genetic*
  • Transglutaminases / metabolism

Substances

  • Chromatin
  • Genetic Markers
  • Histones
  • Ionophores
  • Retinoids
  • Arginine
  • Protein-Arginine N-Methyltransferases
  • Transglutaminases
  • Hydrolases
  • PADI4 protein, human
  • Protein-Arginine Deiminase Type 4
  • Protein-Arginine Deiminases