title: Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A.
abstract: Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common β-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatin-modifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic β-like globin genes and human γ-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances γ-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in β-hemoglobinopathies.
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bauer
authors.forename: Marc A
authors.initials: MA
authors.lastname: Kerenyi
authors.forename: Thuy D
authors.initials: TD
authors.lastname: Vo
authors.forename: Serena
authors.initials: S
authors.lastname: Hou
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Hsu
authors.forename: Huilan
authors.initials: H
authors.lastname: Yao
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Trowbridge
authors.forename: Gail
authors.initials: G
authors.lastname: Mandel
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002853:Chromatography, Liquid; D056970:Co-Repressor Proteins / Q000378:metabolism*; D015672:Erythroid Precursor Cells; D005319:Fetal Hemoglobin / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000494:pharmacology*; D040901:Proteomics; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins; D053719:Tandem Mass Spectrometry; D055544:beta-Globins / Q000378:metabolism
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D002843:Chromatin; D056970:Co-Repressor Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055544:beta-Globins; D005319:Fetal Hemoglobin