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Updated: Jun 6, 2025

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

Ge Zheng1, Maolu Yin1, Stuti Mehta1

  • 1Dana-Farber/Boston Children's Hospital Cancer and Blood Disorder Center, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.

Science (New York, N.Y.)
|November 28, 2024
PubMed

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. 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.

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