Journal
BLOOD
Volume 108, Issue 9, Pages 3179-3186Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-12-010934
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Funding
- NCI NIH HHS [CA101992] Funding Source: Medline
- NCRR NIH HHS [P40 RR012317] Funding Source: Medline
- NHLBI NIH HHS [HL-78276, HL-52243, HL-73442] Funding Source: Medline
- NIDDK NIH HHS [DK-52962] Funding Source: Medline
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High-level induction of fetal (gamma) globin gene expression for therapy of beta-hemoglobinopathies likely requires local chromatin modification and dissociation of repressor complexes for gamma-globin promoter activation. A novel gamma-globin-inducing short-chain fatty acid derivative (SCFAD), RB7, which was identified through computational modeling, produced a 6-fold induction in a reporter assay that detects only strong inducers of the gamma-globin gene promoter and in cultured human erythrold progenitors. To elucidate the molecular mechanisms used by high-potency SCFADs, chromatin immunoprecipitation (Chip) assays performed at the human gamma- and beta-globin gene promoters in GM979 cells and in erythrold progenitors demonstrate that RB7 and butyrate induce dissociation of HDAC3 (but not HDAC1 or HDAC2) and its adaptor protein NCoR, specifically from the gamma-globin gene promoter. A coincident and proportional recruitment of RNA polymerase 11 to the gamma-globin gene promoter was observed with exposure to these gamma-globin inducers. Knockdown of HDAC3 by siRNA induced transcription of the gamma-globin gene promoter, demonstrating that displacement of HDAC3 from the gamma-globin gene promoter by the SCFAD is sufficient to induce gamma-globin gene expression. These studies demonstrate new dynamic alterations in transcriptional regulatory complexes associated with SCFAD-induced activation of the gamma-globin gene and provide a specific molecular target for potential therapeutic intervention.
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