Mi2?-mediated silencing of the fetal ?-globin gene in adult erythroid cells.

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

SUBMITTER: Amaya M 

PROVIDER: S-EPMC3637018 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature