Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin

Curr Opin Genet Dev. 2015 Aug;33:62-70. doi: 10.1016/j.gde.2015.08.001.

Daniel E Bauer ¹, Stuart H Orkin ²

Affiliations

1 Boston Children's Hospital, Boston, MA 02115, United States; Dana-Farber Cancer Institute, Boston, MA 02115, United States; Harvard Medical School, Boston, MA 02115, United States; Harvard Stem Cell Institute, Cambridge, MA 02138, United States. Electronic address: daniel.bauer@childrens.harvard.edu.
2 Boston Children's Hospital, Boston, MA 02115, United States; Dana-Farber Cancer Institute, Boston, MA 02115, United States; Harvard Medical School, Boston, MA 02115, United States; Harvard Stem Cell Institute, Cambridge, MA 02138, United States; Howard Hughes Medical Institute, Boston, MA 02115, United States. Electronic address: stuart_orkin@dfci.harvard.edu.

PMID: 26375765 DOI: 10.1016/j.gde.2015.08.001

Abstract

The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.

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