Induction of human γ globin gene expression by histone deacetylase inhibitors

Cao, Hua; Stamatoyannopoulos, George; Jung, Manfred

doi:10.1182/blood-2003-02-0478

Cited by 79 publications

(64 citation statements)

References 48 publications

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“…6C, a dose-dependent increase in ␥-promoter activity was seen with TSA induction. This finding was consistent with the enhancement of endogenous ␥-gene expression seen with this compound (35,36).…”

Section: Acetylation Stabilizes Nf-e4 Protein By Inhibiting Itssupporting

confidence: 79%

Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1

Zhao

Cumming

Cerruti

et al. 2004

Journal of Biological Chemistry

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Acetylation provides one mechanism by which the functional diversity of individual transcription factors can be expanded. This is valuable in the setting of complex multigene loci that are regulated by a limited number of proteins, such as the human ␤-globin locus. We have studied the role of acetylation in the regulation of the transcription factor NF-E4, a component of a protein complex that facilitates the preferential expression of the human ␥-globin genes in fetal erythroid cells. We have shown that NF-E4 interacts directly with, and serves as a substrate for, the acetyltransferase co-activator PCAF. Acetylation of NF-E4 is restricted to a single residue (Lys 43 ) in the amino-terminal domain of the protein and results in two important functional consequences. Acetylation of NF-E4 prolongs the protein halflife by preventing ubiquitin-mediated degradation. This stabilization is PCAF-dependent, since enforced expression in fetal/erythroid cells of a mutant form of PCAF lacking the histone acetyltransferase domain (PCAF⌬HAT) decreases NF-E4 stability. Acetylation of Lys 43 also reduces the interaction between NF-E4 and HDAC1, potentially maximizing the activating ability of the factor at the ␥-promoter. These results provide further demonstration that co-activators, such as PCAF, can influence individual transcription factor properties at multiple levels to alter their effects on gene expression.

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Section: Acetylation Stabilizes Nf-e4 Protein By Inhibiting Itssupporting

confidence: 79%

Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1

Zhao

Cumming

Cerruti

et al. 2004

Journal of Biological Chemistry

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“…The HDAC6 selective M344 (16b) is a good inducer of terminal cell differentiation in Friend leukemia cells 17 and of γ-globin expression in a promotor assay and in human erythroid cell cultures. 29 Its more HDAC1 selective homologue M360 (16c) mainly exerts an antiproliferative activity in these assays. These findings warrant further investigation of HDAC inhibitor subtype selectivity with respect to biological activity.…”

Section: Discussionmentioning

confidence: 99%

Subtype Selective Substrates for Histone Deacetylases

et al. 2004

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To probe the steric requirements for deacylation, we synthesized lysine-derived small molecule substrates and examined structure-reactivity relationships with various histone deacetylases. Rat liver, human HeLa, and human recombinant class I and II histone deacetylases (HDACs) as well as human recombinant NAD + -dependent SIRT1 (class III enzyme) were used in these studies. A benzyloxycarbonyl substituent on the R-amino group yielded the highest conversion rates. Replacing the -acetyl group with larger lipophilic acyl substituents led to a pronounced decrease in conversion by class I and II enzymes; the class III enzyme displayed a greater tolerance. Incubations with recombinant FLAG-tagged human HDACs 1, 3, and 6 showed a distinct subtype selectivity among small molecule substrates. The subtype selectivity of HDAC inhibitors could be predicted with these substrates and an easily obtainable mixture of HDAC subtypes.

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“…HDAC inhibition has previously been established as a route to fetal hemoglobin induction. Indeed, the observed induction of γ-globin in human subjects treated with sodium butyrate and sodium valproate has been linked to weak HDAC inhibitory activity (22)(23)(24)(25). Despite extensive research in this area, the specific targets among the 18 known human enzymes are not known, in part because of the perceived nonselective action of investigational and tool compounds.…”

Section: Development Of a Miniaturized Assay For Globin Switching In mentioning

confidence: 99%

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

Bradner

Mak

Tanguturi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

185

176

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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.histone | acetylation | hemoglobinopathies | chromatin

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Induction of human γ globin gene expression by histone deacetylase inhibitors

Cited by 79 publications

References 48 publications

Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1

Site-specific Acetylation of the Fetal Globin Activator NF-E4 Prevents Its Ubiquitination and Regulates Its Interaction with the Histone Deacetylase, HDAC1

Subtype Selective Substrates for Histone Deacetylases

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

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