title: Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin.
abstract: Genes encoding human β-type globin undergo a developmental switch from embryonic to fetal to adult-type expression. Mutations in the adult form cause inherited hemoglobinopathies or globin disorders, including sickle cell disease and thalassemia. Some experimental results have suggested that these diseases could be treated by induction of fetal-type hemoglobin (HbF). However, the mechanisms that repress HbF in adults remain unclear. We found that the LRF/ZBTB7A transcription factor occupies fetal γ-globin genes and maintains the nucleosome density necessary for γ-globin gene silencing in adults, and that LRF confers its repressive activity through a NuRD repressor complex independent of the fetal globin repressor BCL11A. Our study may provide additional opportunities for therapeutic targeting in the treatment of hemoglobinopathies.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Manami
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Canver
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Falak
authors.initials: F
authors.lastname: Sher
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Alister P W
authors.initials: AP
authors.lastname: Funnell
authors.affiliation: Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Fisher
authors.affiliation: Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Suciu
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Gabriella E
authors.initials: GE
authors.lastname: Martyn
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Norton
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kurita
authors.affiliation: Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan. Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Children's Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: Merlin
authors.initials: M
authors.lastname: Crossley
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Bauer
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Orkin
authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. peter.kharchenko@post.harvard.edu tmaeda@partners.org.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Kharchenko
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. peter.kharchenko@post.harvard.edu tmaeda@partners.org.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Maeda
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology; D004920:Erythropoiesis / Q000235:genetics; D005319:Fetal Hemoglobin / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D013789:Thalassemia / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055545:gamma-Globins / Q000235:genetics*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C485514:ZBTB7A protein, human; D055545:gamma-Globins; D005319:Fetal Hemoglobin
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