Dynamic posttranscriptional regulation of epsilon-globin gene expression in vivo.
Functional studies of embryonic epsilon-globin indicate that individuals with beta thalassemia or sickle cell disease are likely to benefit from therapeutic, transcriptional derepression of its encoding gene. The success of epsilon-globin gene-reactivation strategies, however, will be tempered by the stability that epsilon-globin mRNA exhibits in developmental stage-discordant definitive erythroid progenitors. Using cell culture and transgenic mouse model systems, we demonstrate that epsilon-globin mRNA is modestly unstable in immature, transcriptionally active erythroid cells, but that this characteristic has relatively little impact on the accumulation of epsilon-globin mRNA at subsequent stages of terminal differentiation. Importantly, the constitutive stability of epsilon-globin mRNA increases in transgenic mouse models of beta thalassemia, suggesting that epsilon- and beta-globin mRNAs are coregulated through a shared posttranscriptional mechanism. As anticipated, relevant cis-acting determinants of epsilon-globin mRNA stability map to its 3' UTR, consistent with the positioning of functionally related elements in other globin mRNAs. These studies demonstrate that posttranscriptional processes do not pose a significant practical barrier to epsilon-globin gene reactivation and, moreover, indicate that related therapeutic strategies may be particularly effective in individuals carrying beta-thalassemic gene defects.
He
Zhenning
Z
Department of Medicine, University of Pennsylvania School of Medicine, and The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104, USA.
Russell
J Eric
JE
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005914:Globins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D017086:beta-Thalassemia / Q000235:genetics*
D012333:RNA, Messenger; D005914:Globins