Abstract
Beta hemoglobinopathies are widely spread monogenic lethal diseases. Delta-globin gene activation has been proposed as a possible approach for curing these pathologies. The therapeutic potential of delta-globin, the non-alpha component of Hemoglobin A2 (α2δ2; HbA2), has been demonstrated in a mouse model of beta thalassemia, while its anti-sickling effect, comparable to that of gamma globin, was established some time ago. Here we show that the delta-globin mRNA level is considerably increased in a Deoxyribonuclease II-alpha knockout mouse model in which type 1 interferon (interferon beta, IFNb) is activated. IFNb activation in the fetal liver improves the delta-globin mRNA level, while the beta-globin mRNA level is significantly reduced. In addition, we show that HbA2 is significantly increased in patients with multiple sclerosis under type 1 interferon treatment. Our results represent a proof of principle that delta-globin expression can be enhanced through the use of molecules. This observation is potentially interesting in view of a pharmacological approach able to increase the HbA2 level.
Highlights
Modulations of Fetal-hemoglobin (HbF) and possibly hemoglobin-A2 (HbA2) are of interest given their potential roles in ameliorating beta thalassemia and sickle cell anemia phenotypes [1,2,3,4].Recently, through genome-wide association studies (GWASs) in the SardiNIA cohort, Danjou et al identified new variants associated with levels of HbF, HbA1 (Hemoglobin A1), and HbA2 [5]
In the regional association plots, at the loci associated with HbF reported by the authors [5], we noticed some suggestive, not genome wide significant, signals covering a region on chromosome 19 were two genes related to erythropoiesis are present: Krüppel-like factor 1 (Klf1) and Deoxyribonuclease II-alpha (DNase2a)
We aimed to evaluate the possible effect of DNase2a deficiency on human beta-like globin gene expression in vivo
Summary
Modulations of Fetal-hemoglobin (HbF) and possibly hemoglobin-A2 (HbA2) are of interest given their potential roles in ameliorating beta thalassemia (beta thal) and sickle cell anemia phenotypes [1,2,3,4].Recently, through genome-wide association studies (GWASs) in the SardiNIA cohort, Danjou et al identified new variants associated with levels of HbF, HbA1 (Hemoglobin A1), and HbA2 [5]. In the regional association plots, at the loci associated with HbF reported by the authors [5], we noticed some suggestive, not genome wide significant, signals covering a region on chromosome 19 were two genes related to erythropoiesis are present: Krüppel-like factor 1 (Klf1) and Deoxyribonuclease II-alpha (DNase2a). The effect of Klf on HbF, HbA1, and HbA2 expression has been largely elucidated [6,7,8,9], while a possible effect of DNase2a on hemoglobins expression has not yet been investigated [10, 11]. DNase2a is expressed in the central macrophage of erythroblastic islands (CMEI), where it is involved in the digestion of extruded nuclei of developing erythrocytes [10, 12]. Ifnar KO rescues the impaired erythropoiesis of the DNase2a KO phenotype [12]
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