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

An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate beta-type globin gene disorders such as sickle cell anemia and beta-thalassemia through activation of the fetal gamma-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in gamma-globin gene silencing, and Mi2 beta (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2 beta relieves gamma-globin gene silencing in beta-YAC transgenic murine chemical inducer of dimerization 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, Mi2 beta binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for gamma-globin gene silencing during beta-type globin gene switching. Remarkably, <50% knockdown of Mi2 beta is sufficient to significantly induce gamma-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2 beta is a potential target for therapeutic induction of fetal hemoglobin.