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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3179-3186.
Prepublished online as a Blood First Edition Paper on July 18, 2006; DOI 10.1182/blood-2005-12-010934.
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RED CELLS
Short-chain fatty acids induce  -globin gene expression by displacement of a HDAC3-NCoR repressor complex
Rishikesh Mankidy,
Douglas V. Faller,
Rodwell Mabaera,
Christopher H. Lowrey,
Michael S. Boosalis,
Gary L. White,
Serguei A. Castaneda, and
Susan P. Perrine
From Gene Regulation Laboratories, Inc, Newton, MA; the Cancer Center and Hemoglobinopathy–Thalassemia Research Unit, Departments of Medicine, Pediatrics, Pharmacology, and Experimental Therapeutics, Boston University School of Medicine, Boston, MA; the University of Oklahoma Health Sciences Center, Oklahoma City, OK; and the Departments of Medicine and Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH.
High-level induction of fetal ( ) globin gene expression for therapy of  -hemoglobinopathies likely requires local chromatin modification and dissociation of repressor complexes for -globin promoter activation. A novel -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 -globin gene promoter and in cultured human erythroid progenitors. To elucidate the molecular mechanisms used by high-potency SCFADs, chromatin immunoprecipitation (ChIP) assays performed at the human - and -globin gene promoters in GM979 cells and in erythroid progenitors demonstrate that RB7 and butyrate induce dissociation of HDAC3 (but not HDAC1 or HDAC2) and its adaptor protein NCoR, specifically from the -globin gene promoter. A coincident and proportional recruitment of RNA polymerase II to the -globin gene promoter was observed with exposure to these -globin inducers. Knockdown of HDAC3 by siRNA induced transcription of the -globin gene promoter, demonstrating that displacement of HDAC3 from the -globin gene promoter by the SCFAD is sufficient to induce -globin gene expression. These studies demonstrate new dynamic alterations in transcriptional regulatory complexes associated with SCFAD-induced activation of the -globin gene and provide a specific molecular target for potential therapeutic intervention.
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