Blood Journal
Leading the way in experimental and clinical research in hematology

Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells

  1. Maria Amaya,
  2. Megha Desai,
  3. Merlin Nithya Gnanapragasam,
  4. Shou Zhen Wang,
  5. Sheng Zu Zhu,
  6. David C. Williams Jr., and
  7. Gordon D. Ginder*
  1. 1 Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, United States
  1. * Corresponding author; email: gdginder{at}

Key points

  • Mi2β exerts a major part of its silencing effect on embryonic and fetal globin genes by positively regulating the BCL11A and KLF1 genes

  • Partial depletion of Mi2β induces increased γ-globin gene expression in primary human erythroid cells without impairing differentiation


An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine CID hematopoietic cells and in CD34+ progenitor derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, less than 50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34+ progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin.

  • Submitted November 7, 2012.
  • Accepted February 19, 2013.