title: Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.
abstract: Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vijay G
authors.initials: VG
authors.lastname: Sankaran
authors.forename: Tobias F
authors.initials: TF
authors.lastname: Menne
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Akie
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lettre
authors.forename: Ben
authors.initials: B
authors.lastname: Van Handel
authors.forename: Hanna K A
authors.initials: HK
authors.lastname: Mikkola
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Alan B
authors.initials: AB
authors.lastname: Cantor
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D004900:Erythroblasts / Q000378:metabolism; D041905:Erythroid Cells / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D004920:Erythropoiesis; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation; D006453:Hemoglobinopathies / Q000628:therapy; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D051379:Mice; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D014157:Transcription Factors; C498432:ZFPM1 protein, human; D055544:beta-Globins; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex