Down-regulation of Myc is essential for terminal erythroid maturation

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G1 phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G1-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.

Detaljer

Författare
  • Senthil Raja Jayapal
  • Kian Leong Lee
  • Peng Ji
  • Philipp Kaldis
  • Bing Lim
  • Harvey F. Lodish
Externa organisationer
  • National University of Singapore
  • Whitehead Institute for Biomedical Research
  • Institute of Molecular and Cell Biology
  • Harvard Medical School
  • Genome Institute of Singapore
Originalspråkengelska
Sidor (från-till)40252-40265
TidskriftJournal of Biological Chemistry
Volym285
Utgåva nummer51
StatusPublished - 2010 dec 17
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa