title: Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2.
abstract: Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF) is a promising approach for ameliorating sickle cell disease (SCD) and β-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC) 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2), elicits a dose and time dependent induction of γ-globin mRNA (HBG) and HbF in cultured primary cells derived from healthy individuals and sickle cell patients. Gene expression profiling of erythroid progenitors treated with ACY-957 identified global changes in gene expression that were significantly enriched in genes previously shown to be affected by HDAC1 or 2 knockdown. These genes included GATA2, which was induced greater than 3-fold. Lentiviral overexpression of GATA2 in primary erythroid progenitors increased HBG, and reduced adult β-globin mRNA (HBB). Furthermore, knockdown of GATA2 attenuated HBG induction by ACY-957. Chromatin immunoprecipitation and sequencing (ChIP-Seq) of primary erythroid progenitors demonstrated that HDAC1 and 2 occupancy was highly correlated throughout the GATA2 locus and that HDAC1/2 inhibition led to elevated histone acetylation at well-known GATA2 autoregulatory regions. The GATA2 protein itself also showed increased binding at these regions in response to ACY-957 treatment. These data show that chemical inhibition of HDAC1/2 induces HBG and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of the GATA2 gene.
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: Jeffrey R
authors.identifier: http://orcid.org/0000-0002-6875-1826
authors.initials: JR
authors.lastname: Shearstone
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: Olga
authors.initials: O
authors.lastname: Golonzhka
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: Apurva
authors.initials: A
authors.lastname: Chonkar
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Tamang
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: van Duzer
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Jones
authors.affiliation: Acetylon Pharmaceuticals Inc., Boston, MA, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Jarpe
mesh_terms: D000755:Anemia, Sickle Cell / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000187:drug effects* / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000378:metabolism*; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D056572:Histone Deacetylase Inhibitors; D055544:beta-Globins; D005319:Fetal Hemoglobin; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2