2. Academic Validation
  3. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

  • Science. 2016 Jan 15;351(6270):285-9. doi: 10.1126/science.aad3312.
Takeshi Masuda 1,  Xin Wang 2,  Manami Maeda 1,  Matthew C Canver 3,  Falak Sher 3,  Alister P W Funnell 4,  Chris Fisher 5,  Maria Suciu 5,  Gabriella E Martyn 4,  Laura J Norton 4,  Catherine Zhu 1,  Ryo Kurita 6,  Yukio Nakamura 7,  Jian Xu 8,  Douglas R Higgs 5,  Merlin Crossley 4,  Daniel E Bauer 3,  Stuart H Orkin 9,  Peter V Kharchenko 10,  Takahiro Maeda 11
Affiliations

Affiliations

  • 1 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
  • 3 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.
  • 4 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
  • 5 Medical Research Council, Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
  • 6 Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan.
  • 7 Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, Japan. Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan.
  • 8 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.
  • 9 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.
  • 10 Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA. [email protected] [email protected].
  • 11 Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. [email protected] [email protected].
PMID: 26816381 DOI: 10.1126/science.aad3312
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.

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