title: Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
abstract: 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.
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute Technology, Cambridge, MA 02142, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.forename: Raymond
authors.initials: R
authors.lastname: Mak
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Tanguturi
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ross
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Chang
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Bosco
authors.forename: Nathan
authors.initials: N
authors.lastname: West
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Morse
authors.forename: Katherine
authors.initials: K
authors.lastname: Lin
authors.forename: John Paul
authors.initials: JP
authors.lastname: Shen
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Kwiatkowski
authors.forename: Nele
authors.initials: N
authors.lastname: Gheldof
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000349:Africa; D002454:Cell Differentiation / Q000235:genetics; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007223:Infant; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference
chemical_list: D056572:Histone Deacetylase Inhibitors; D020033:Protein Isoforms; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2