A post‐transcriptional process contributes to efficient γ‐globin gene silencing in definitive erythroid cells

Objectives:  The expression of human γ globin is developmentally regulated through mechanisms that affect the transcriptional activity of its encoding gene. The current manuscript investigates whether the efficiency of this process might be enhanced though an unrecognized post‐transcriptional event that defines the stability of γ‐globin mRNA. Methods:  Experiments were conducted in vivo in transgenic mice expressing human γ globin in their adult erythroid cells. The expression of γ‐globin protein was manipulated by breeding the transgene into animals producing different levels of endogenous mouse β‐globin. Changes in the expression of γ globin were then correlated to measures of γ‐globin mRNA stability in vivo . Results:  Human γ globin was expressed at higher levels in thalassemic than in than non‐thalassemic control transgenics, paralleling a highly significant increase in the stability of γ‐globin mRNA. Other molecular events–including possible transcriptional induction of the transgene, or an increase in the stability of the γ‐globin protein–did not appear to contribute to the observed increase in transgene expression. As anticipated, the stability of γ‐globin mRNA also fell in bitransgenic animals that co‐expressed human β‐globin mRNA. Conclusions:  Our results are consistent with a model for dynamic post‐transcriptional control of γ‐globin gene expression, through modulation of the stability of its encoding mRNA. Moreover, the stability of γ‐globin mRNA appears to be inversely related to ambient levels of co‐expressed β‐globin mRNA. This data suggests that therapeutic gene‐reactivation and/or gene‐replacement therapies may be particularly effective in individuals with severe forms of β‐thalassemia.