Induction of human fetal hemoglobin expression by adenosine-2’,3’-dialdehyde

Yinghong He,Renxiang Tan,Junyi Ju,Miaomiao Zhang,Ronghua Liu,Gerhard Rank,Fiona Brown,Zhen Xu,Loretta Cerruti,Chi Ma,Stephen M Jane,Quan Zhao

doi:10.1186/1479-5876-11-14

Abstract

BackgroundPharmacologic reactivation of fetal hemoglobin expression is a promising strategy for treatment of sickle cell disease and β-thalassemia. The objective of this study was to investigate the effect of the methyl transferase inhibitor adenosine-2’,3’-dialdehyde (Adox) on induction of human fetal hemoglobin (HbF) in K562 cells and human hematopoietic progenitor cells.MethodsExpression levels of human fetal hemoglobin were assessed by northern blot analysis and Real-time PCR. HbF and adult hemoglobin (HbA) content were analyzed using high-performance liquid chromatography (HPLC). DNA methylation levels on human gamma-globin gene promoters were determined using Bisulfite sequence analysis. Enrichment of histone marks on genes was assessed by chromosome immunoprecipitation (ChIP).ResultsAdox induced γ-globin gene expression in both K562 cells and in human bone marrow erythroid progenitor cells through a mechanism potentially involving inhibition of protein arginine methyltransferase 5 (PRMT5).ConclusionsThe ability of methyl transferase inhibitors such as Adox to efficiently reactivate fetal hemoglobin expression suggests that these agents may provide a means of reactivating fetal globin expression as a therapeutic option for treating sickle cell disease and β-thalassemia.

Highlights

Pharmacologic reactivation of fetal hemoglobin expression is a promising strategy for treatment of sickle cell disease and β-thalassemia
We determined that protein arginine methyltransferase 5 (PRMT5) coupled with Dnmt3a and related complexes played a critical role in human fetal globin gene repression [7,8]
In order to test the effect of Adox to induce γ-globin, K562 cells were treated and showed a dose response effect on activation (Figure 1A)

Summary

Introduction

Pharmacologic reactivation of fetal hemoglobin expression is a promising strategy for treatment of sickle cell disease and β-thalassemia. Reactivation of fetal hemoglobin (HbF) in adults is one of the most effective strategies for treatment of sickle cell disease and β-thalassemia as increased fetal globin levels are associated with improved symptoms in hemoglobinopathy patients [2]. We have found that treatment with adenosine-2,’3’-dialdehyde (Adox), a methyltransferase inhibitor [9,10], can induce fetal hemoglobin gene transcription in adult human bone marrow erythroid progenitor cells. This activity of Adox may be associated with inhibition of PRMT5

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Conclusion