Language
English
Publication Date
11-29-2024
Journal
Science
DOI
10.1126/science.adp3025
PMID
39607926
PMCID
PMC12924673
PubMedCentral® Posted Date
2-22-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Down-regulation of BCL11A protein reverses the fetal (HbF, α2γ2) to adult (HbA, α2β2) 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 γ-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.
Keywords
Animals, Humans, Mice, Erythroid Cells, Fetal Hemoglobin, gamma-Globins, Gene Silencing, Nuclear Proteins, Protein Multimerization, Protein Stability, Repressor Proteins, Zinc Fingers
Published Open-Access
yes
Recommended Citation
Zheng, Ge; Yin, Maolu; Mehta, Stuti; et al., "A Tetramer of BCL11A Is Required for Stable Protein Production and Fetal Hemoglobin Silencing" (2024). Faculty, Staff and Students Publications. 7182.
https://digitalcommons.library.tmc.edu/baylor_docs/7182