title: Strict in vivo specificity of theBcl11aerythroid enhancer.
abstract: BCL11A, a repressor of human fetal (γ-)globin expression, is required for immune and hematopoietic stem cell functions and brain development. Regulatory sequences within the gene, which are subject to genetic variation affecting fetal globin expression, display hallmarks of an erythroid enhancer in cell lines and transgenic mice. As such, this enhancer is a novel, attractive target for therapeutic gene editing. To explore the roles of such sequences in vivo, we generated mice in which the orthologous 10-kb intronic sequences were removed.Bcl11aenhancer-deleted mice,Bcl11a(Δenh), phenocopy the BCL11A-null state with respect to alterations of globin expression, yet are viable and exhibit no observable blood, brain, or other abnormalities. These preclinical findings provide strong in vivo support for genetic modification of the enhancer for therapy of hemoglobin disorders.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Elenoe C
authors.identifier: 0000-0003-1700-5396
authors.initials: EC
authors.lastname: Smith
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Sidinh
authors.initials: S
authors.lastname: Luc
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Donyell M
authors.initials: DM
authors.lastname: Croney
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Stem Cell and Regenerative Biology and.|Center for Brain Science, Harvard University, Cambridge, MA; and.
authors.forename: Mollie B
authors.identifier: 0000-0003-2130-2289
authors.initials: MB
authors.lastname: Woodworth
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Stem Cell and Regenerative Biology and.|Center for Brain Science, Harvard University, Cambridge, MA; and.
authors.forename: Luciano C
authors.initials: LC
authors.lastname: Greig
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.|Howard Hughes Medical Institute, Boston, MA.
authors.forename: Yuko
authors.identifier: 0000-0003-3260-2957
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Minh
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Falak
authors.initials: F
authors.lastname: Sher
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Stem Cell and Regenerative Biology and.|Center for Brain Science, Harvard University, Cambridge, MA; and.
authors.forename: Jeffrey D
authors.identifier: 0000-0001-7353-3877
authors.initials: JD
authors.lastname: Macklis
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.
authors.forename: Daniel E
authors.identifier: 0000-0001-5076-7945
authors.initials: DE
authors.lastname: Bauer
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.|Harvard Stem Cell Institute, Harvard University, Cambridge, MA.|Department of Pediatrics, Harvard Medical School, Boston, MA.|Howard Hughes Medical Institute, Boston, MA.
authors.forename: Stuart H
authors.identifier: 0000-0002-0313-152X
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D002451:Cell Compartmentation; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D041905:Erythroid Cells / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism*; D012097:Repressor Proteins
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005319:Fetal Hemoglobin