Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

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Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease

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dc.contributor.author Bradner, James Elliott
dc.contributor.author Mak, Raymond Heungwing
dc.contributor.author Tanguturi, Shyam Kumar
dc.contributor.author Mazitschek, Ralph
dc.contributor.author Haggarty, Stephen John
dc.contributor.author Ross, Kenneth N
dc.contributor.author Chang, Cindy Y.
dc.contributor.author Bosco, Jocelyn
dc.contributor.author West, Nathan
dc.contributor.author Morse, Elizabeth
dc.contributor.author Lin, Katherine
dc.contributor.author Shen, John Paul
dc.contributor.author Kwiatkowski, Nicholas Paul
dc.contributor.author Gheldof, Nele
dc.contributor.author Dekker, Job
dc.contributor.author DeAngelo, Daniel J.
dc.contributor.author Carr, Steven A.
dc.contributor.author Schreiber, Stuart L.
dc.contributor.author Golub, Todd Robert
dc.contributor.author Ebert, Benjamin L.
dc.date.accessioned 2016-11-16T20:54:08Z
dc.date.issued 2010
dc.identifier.citation Bradner, James E., Raymond Mak, Shyam K. Tanguturi, Ralph Mazitschek, Stephen J. Haggarty, Kenneth Ross, Cindy Y. Chang, et al. 2010. “Chemical Genetic Strategy Identifies Histone Deacetylase 1 (HDAC1) and HDAC2 as Therapeutic Targets in Sickle Cell Disease.” Proceedings of the National Academy of Sciences 107 (28) (June 28): 12617–12622. doi:10.1073/pnas.1006774107. en_US
dc.identifier.issn 0027-8424 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:29400932
dc.description.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. en_US
dc.language.iso en_US en_US
dc.publisher Proceedings of the National Academy of Sciences en_US
dc.relation.isversionof doi:10.1073/pnas.1006774107 en_US
dc.relation.hasversion https://www.ncbi.nlm.nih.gov/pubmed/20616024 en_US
dash.license LAA
dc.subject Histone en_US
dc.subject Acetylation en_US
dc.subject Homoglobinopathies en_US
dc.subject Chromatin en_US
dc.title Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dash.depositing.author Mak, Raymond Heungwing
dc.date.available 2016-11-16T20:54:08Z

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