A Tetramer of BCL11A is Required for Stable Protein Production and Fetal Hemoglobin Silencing

Down-regulation of BCL11A protein reverses the fetal (HbF, a2g2) to adult (HbA, a2β2) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Due to reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop novel small molecule approaches, we interrogated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc-finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for g-globin gene repression, as an engineered monomer fails to engage a critical corepressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing, and provide opportunities for drug discovery.