Mi2b-mediated silencing of the fetal g-globin gene in adult erythroid cells

An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate b-type globin gene disorders such as sickle cell anemia and b-thalassemia through activation of the fetal g-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in g-globin gene silencing, and Mi2b (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2b relieves g-globin gene silencing in b-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34¹ progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2b binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for g-globin gene silencing during b-type globin gene switching. Remarkably, <50% knockdown of Mi2b is sufficient to significantly induce g-globin gene expression without disrupting erythroid differentiation of primary human CD34¹ progenitors. These results indicate that Mi2b is a potential target for therapeutic induction of fetal hemoglobin. (Blood.