Submitted June 8, 2006
Accepted August 23, 2006
Dynamic post-transcriptional regulation of
-globin gene expression in vivo
Zhenning He and J. Eric Russell*
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA
* Corresponding author; email: russell{at}email.chop.edu.
Functional studies of embryonic 
-globin indicate that individuals with 
thalassemia or sickle-cell disease are likely to benefit from therapeutic, transcriptional derepression of its encoding gene. The success of -globin gene-reactivation strategies, however, will be tempered by the stability that -globin mRNA exhibits in developmental stage-discordant definitive erythroid progenitors. Using cell culture and transgenic mouse model systems, we demonstrate that -globin mRNA is modestly unstable in immature, transcriptionally active erythroid cells, but that this characteristic has relatively little impact on the accumulation of -globin mRNA at subsequent stages of terminal differentiation. Importantly, the constitutive stability of -globin mRNA increases in transgenic mouse models of thalassemia, suggesting that - and -globin mRNAs are co-regulated through a shared post-transcriptional mechanism. As anticipated, relevant cis-acting determinants of -globin mRNA stability map to its 3'UTR, consistent with the positioning of functionally related elements in other globin mRNAs. These studies demonstrate that post-transcriptional processes do not pose a significant practical barrier to -globin gene reactivation and, moreover, indicate that related therapeutic strategies may be particularly effective in individuals carrying -thalassemic gene defects.
