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