Submitted January 11, 2006
Accepted July 4, 2006
Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves 
-globin activation by CREB1 and ATF-2
Jose Sangerman, Moo Seung Lee, Xiao Yao, Eugene Oteng, Cheng-Hui Hsiao, Wei Li, Sima Zein, Solomon F Ofori-Acquah, and Betty S Pace*
Yale University, Department of Pediatrics, Yale University, New Haven, CT, USA
University of Texas at Dallas, Department of Molecular and Cell Biology, Richardson, TX, USA
University of South Alabama, Department of Cell Biology and Neuroscience, Mobile, AL, USA
* Corresponding author; email: bpace{at}utdallas.edu.
The histone deacetylase inhibitors (HDACIs) butyrate and trichostatin A activate 
-globin expression via a p38 mitogen activating protein kinase-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 G-globin promoter (G-CRE) in vitro after drug treatments; subsequent chromatin immunoprecipitation assays confirmed ATF-2 and CREB1 binding to the G-CRE in vivo. Enforced expression of ATF-2 and CREB produced G-promoter trans-activation which was abolished by a two base pair mutation in the putative G-CRE. The data presented herein demonstrates that -gene induction by butyrate and trichostatin A involves ATF-2 and CREB1 activation via p38 MAPK signaling.
