Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2.
The histone deacetylase inhibitors (HDA-CIs) butyrate and trichostatin A activate gamma-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that down-stream 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 (G)gamma-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 (G)gamma-promoter trans-activation which was abolished by a 2-base pair mutation in the putative G-CRE. The data presented herein demonstrate that gamma-gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling.
Sangerman
Jose
J
Department of Pediatrics, Yale University, New Haven, CT, USA.
Lee
Moo Seung
MS
Yao
Xiao
X
Oteng
Eugene
E
Hsiao
Cheng-Hui
CH
Li
Wei
W
Zein
Sima
S
Ofori-Acquah
Solomon F
SF
Pace
Betty S
BS
D051698:Activating Transcription Factor 2 / Q000378:metabolism / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005319:Fetal Hemoglobin / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D010766:Phosphorylation / Q000187:drug effects; D015533:Transcriptional Activation; D005719:gamma-Globulins / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D051698:Activating Transcription Factor 2; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D005719:gamma-Globulins; D005319:Fetal Hemoglobin; D048051:p38 Mitogen-Activated Protein Kinases