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

Daniel E Bauer, Stuart H Orkin

Journal: Current opinion in genetics & development 2016;33():62-70

PMID: 26375765

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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.

Address: 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: [email protected].; 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: [email protected].

DOI: 10.1016/j.gde.2015.08.001

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MeSH Terms: Anemia, Sickle Cell, Carrier Proteins, Fetal Hemoglobin, Gene Expression Regulation, Genome-Wide Association Study, Humans, Nuclear Proteins, Repressor Proteins, beta-Globins, beta-Thalassemia