A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing

• 成果类型: Article
• 署名作者: Zheng, Ge; Yin, Maolu; Mehta, Stuti; Chu, I-Te; Wang, Stacy; Alshaye, Alia; Drainville, Kirstin; Buyanbat, Altantsetseg; Bienfait, Frederique; Tenglin, Karin; Zhu, Qian; Orkin, Stuart H.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Howard Hughes Medical Institute; Harvard University; Harvard Medical School; Baylor College of Medicine
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13606
• DOI: 10.1126/science.adp3025
• 发表日期: 2024-11-29
• 页码: 1010-1018
• 关键词: greek hereditary persistence; sickle-cell-disease; gamma-globin gene; transcription factors; expression; FAMILY; association; proteasome; enhancer; MODEL

摘要

Down-regulation of BCL11A protein reverses the fetal (HbF, alpha 2 gamma 2) to adult (HbA, alpha 2 beta 2) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated 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 gamma-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery.