Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 28, Pages 12617-12622Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1006774107
Keywords
histone; acetylation; hemoglobinopathies; chromatin
Categories
Funding
- National Institutes of Health (NIH) [5R01 HG003945]
- Burroughs-Wellcome
- NIH [1K08CA128972, GM38627, HG003143]
- American Society of Hematology (ASH)
- Burroughs-Wellcome Foundation
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The worldwide burden of sickle cell disease is enormous, with over 200,000 infants born with the disease each year in Africa alone. Induction of fetal hemoglobin is a validated strategy to improve symptoms and complications of this disease. The development of targeted therapies has been limited by the absence of discrete druggable targets. We developed a unique bead-based strategy for the identification of inducers of fetal hemoglobin transcripts in primary human erythroid cells. A small-molecule screen of bioactive compounds identified remarkable class-associated activity among histone deacetylase (HDAC) inhibitors. Using a chemical genetic strategy combining focused libraries of biased chemical probes and reverse genetics by RNA interference, we have identified HDAC1 and HDAC2 as molecular targets mediating fetal hemoglobin induction. Our findings suggest the potential of isoform-selective inhibitors of HDAC1 and HDAC2 for the treatment of sickle cell disease.
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