title: Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin.
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.
authors.affiliation: 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.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bauer
authors.affiliation: 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.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002352:Carrier Proteins / Q000235:genetics*; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics*; D012097:Repressor Proteins; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism; D017086:beta-Thalassemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055544:beta-Globins; D005319:Fetal Hemoglobin