Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2

Jose Sangerman, Seung Lee Moo, Xiao Yao, Eugene Oteng, Cheng Hui Hsiao, Wei Li, Sima Zein, Solomon F. Ofori-Acquah, Betty Sue Pace

Research output: Contribution to journalArticle

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Abstract

The histone deacetylase inhibitors (HDACIs) butyrate and trichostatin A activate γ-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that downstream effectors of p38 MAPK, namely activating transcription factor-2 (ATF-2) and cyclic AMP response element (CRE) binding protein (CREB), are intimately involved in fetal hemoglobin induction by these agents. In this study, we observed increased ATF-2 and CREB1 phosphorylation mediated by the HDACIs in K562 cells, in conjunction with histone H4 hyperacetylation. Moreover, enhanced DNA-protein interactions occurred in the CRE in the Gγ-globin promoter (G-CRE) in vitro after drug treatments; subsequent chromatin immunoprecipitation assay confirmed ATF-2 and CREB1 binding to the G-CRE in vivo. Enforced expression of ATF-2 and CREB produced Gγ-promoter trans-activation which was abolished by a 2-base pair mutation in the putative G-CRE. The data presented herein demonstrate that γ-gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling.

Original languageEnglish (US)
Pages (from-to)3590-3599
Number of pages10
JournalBlood
Volume108
Issue number10
DOIs
StatePublished - Nov 15 2006

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Activating Transcription Factor 2
Fetal Hemoglobin
Histone Deacetylase Inhibitors
Globins
Response Elements
Cyclic AMP
Chemical activation
trichostatin A
Mitogens
Protein Kinases
Butyrates
Drug therapy
Cyclic AMP Response Element-Binding Protein
Phosphorylation
K562 Cells
Chromatin Immunoprecipitation
Base Pairing
Histones
Chromatin
Assays

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2. / Sangerman, Jose; Moo, Seung Lee; Yao, Xiao; Oteng, Eugene; Hsiao, Cheng Hui; Li, Wei; Zein, Sima; Ofori-Acquah, Solomon F.; Pace, Betty Sue.

In: Blood, Vol. 108, No. 10, 15.11.2006, p. 3590-3599.

Research output: Contribution to journalArticle

Sangerman, J, Moo, SL, Yao, X, Oteng, E, Hsiao, CH, Li, W, Zein, S, Ofori-Acquah, SF & Pace, BS 2006, 'Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2', Blood, vol. 108, no. 10, pp. 3590-3599. https://doi.org/10.1182/blood-2006-01-023713
Sangerman, Jose ; Moo, Seung Lee ; Yao, Xiao ; Oteng, Eugene ; Hsiao, Cheng Hui ; Li, Wei ; Zein, Sima ; Ofori-Acquah, Solomon F. ; Pace, Betty Sue. / Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves γ-globin activation by CREB1 and ATF-2. In: Blood. 2006 ; Vol. 108, No. 10. pp. 3590-3599.
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