DOI: 10.1182/blood.v90.5.2075. Induction of γ-Globin by Histone Deacetylase Inhibitors

Induction of γ-Globin by Histone Deacetylase Inhibitors

10.1182/blood.v90.5.2075

Crossref journal-article

American Society of Hematology

Blood (234)

Abstract

AbstractThe short-chain fatty acid butyrate has been shown to elevate fetal hemoglobin (HbF ) by inducing expression of the γ-globin gene. Regulation of gene expression by butyrate is thought to proceed via inhibition of the enzyme histone deacetylase, leading to elevated levels of core histone acetylation which affect chromatin structure and transcription rates. To determine whether changes in histone acetylation are critical for the regulation of the γ-globin gene, we tested three potent and specific inhibitors of histone deacetylase, the cyclic tetrapeptides trapoxin and Helminthsporium carbonum toxin (HC toxin), and the antifungal antibiotic trichostatin A for their ability to induce fetal hemoglobin expression in erythroid cells. These compounds induced fetal hemoglobin in both primary erythroid cell cultures and human erythroleukemia (K562) cells. A butyrate-responsive element spanning the duplicated CCAAT box region of the γ-globin promoter has been identified in transient transfection assays using a reporter construct in K562 cells, and we show that the same promoter region is required for response to trapoxin and trichostatin. Mutational analysis of the γ-globin promoter indicates that the distal CCAAT box and 3′ flanking sequence (CCAATAGCC) is critical for activation by butyrate, trapoxin, and trichostatin, whereas the proximal element (CCAATAGTC) plays a less important role. These results show that inhibition of histone deacetylase can lead to transcriptional activation of γ-globin promoter reporter gene constructs through proximal promoter elements, and suggest that butyrate induces γ-globin expression via such changes in histone acetylation.

Bibliography

McCaffrey, P. G., Newsome, D. A., Fibach, E., Yoshida, M., & Su, M. S.-S. (1997). Induction of Î³-Globin by Histone Deacetylase Inhibitors. Blood, 90(5), 2075â2083.

Authors 5

Patricia G. McCaffrey (first)
David A. Newsome (additional)
Eitan Fibach (additional)
Minoru Yoshida (additional)
Michael S.-S. Su (additional)

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Dates

Type	When
Created	5 years, 10 months ago (Oct. 12, 2019, 4:13 p.m.)
Deposited	2 years, 10 months ago (Oct. 1, 2022, 11:48 a.m.)
Indexed	2 months, 4 weeks ago (May 30, 2025, 6:23 a.m.)
Issued	27 years, 11 months ago (Sept. 1, 1997)
Published	27 years, 11 months ago (Sept. 1, 1997)
Published Print	27 years, 11 months ago (Sept. 1, 1997)

Funders 0

None

BibTeX

@article{McCaffrey_1997, title={Induction of γ-Globin by Histone Deacetylase Inhibitors}, volume={90}, ISSN={0006-4971}, url={http://dx.doi.org/10.1182/blood.v90.5.2075}, DOI={10.1182/blood.v90.5.2075}, number={5}, journal={Blood}, publisher={American Society of Hematology}, author={McCaffrey, Patricia G. and Newsome, David A. and Fibach, Eitan and Yoshida, Minoru and Su, Michael S.-S.}, year={1997}, month=sep, pages={2075–2083} }

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