A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing
Down-regulation of BCL11A protein reverses the fetal (HbF, α<sub>2</sub>γ<sub>2</sub>) to adult (HbA, α<sub>2</sub>β<sub>2</sub>) 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 γ-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.
Authors
- Altantsetseg Buyanbat
- Maolu Yin (ORCID: https://orcid.org/0000-0001-9899-0089)
- Stacy Wang
- I-Te Chu (ORCID: https://orcid.org/0000-0002-2235-3275)
- Stuart H. Orkin (ORCID: https://orcid.org/0000-0002-0313-152X)
- Stuti Mehta (ORCID: https://orcid.org/0000-0002-6810-6771)
- Karin Tenglin (ORCID: https://orcid.org/0000-0002-1318-8204)
- Qian Zhu (ORCID: https://orcid.org/0000-0001-7062-8221)
- Ge Zheng (ORCID: https://orcid.org/0000-0002-2369-1276)
- Alia Alshaye (ORCID: https://orcid.org/0009-0000-2988-8232)
- Kirstin Drainville
- Frédérique Bienfait
Institutions
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Baylor College of Medicine (US)
- Baylor Genetics (US)
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
Publication Details
- Journal
- Science
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1126/science.adp3025
- Citations
- 13
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 5.69