Exploring epigenetic and microRNA approaches for γ-globin gene regulation

Abstract

Therapeutic interventions aimed at inducing fetal hemoglobin and reducing the concentration of sickle hemoglobin is an effective approach to ameliorating acute and chronic complications of sickle cell disease, exemplified by the long-term use of hydroxyurea. However, there remains an unmet need for the development of additional safe and effective drugs for single agent or combination therapy for individuals with β-hemoglobinopathies. Regulation of the γ-globin to β-globin switch is achieved by chromatin remodeling at the HBB locus on chromosome 11 and interactions of major DNA binding proteins, such as KLF1 and BCL11A in the proximal promoters of the globin genes. Experimental evidence also supports a role of epigenetic modifications including DNA methylation, histone acetylation/methylation, and microRNA expression in γ-globin gene silencing during development. In this review, we will critically evaluate the role of epigenetic mechanisms in γ-globin gene regulation and discuss data generated in tissue culture, pre-clinical animal models, and clinical trials to support drug development to date. The question remains whether modulation of epigenetic pathways will produce sufficient efficacy and specificity for fetal hemoglobin induction and to what extent targeting these pathways form the basis of prospects for clinical therapy.

Keywords: DNA methylation; Epigenetics; fetal hemoglobin; histone acetylation; microRNA; sickle cell disease.

Figure 1.

Effect of epigenetic mechanisms, miRNAs, and transcription factors on fetal globin gene expression during hemoglobin switching. Shown is the HBB gene locus on chromosome 11 which consists of the five developmentally regulated globin genes, including fetal γ-globin (green) and adult β-globin (purple). Silencing of γ-globin genes is mediated by transcriptional repressors MYB which activates KLF1, which in turn activates the repressor BCL11A which mediates transcriptional silencing of γ-globin. The γ-globin promoters become hypermethylated and silenced by DNMT1. The DNMT3 proteins, DNMT3A and DNMT3B, are required for long-term methylation of the γ-globin gene promoters and silencing during adult erythropoiesis. In addition, deacetylation by HDAC1/2 inhibits γ-globin expression and activates adult HBB expression. MiR-29b, a DNMT3 inhibitor, inhibits MYB expression resulting in γ-globin gene activation. Additional miRNAs that inhibit (red line) or induce (green line) HbF are shown. (A color version of this figure is available in the online journal.) DNMT: DNA methyltransferase; BCL11A; B-cell lymphoma 11A; HSs: hypersensitive sites, KLF1; Krüppel-like factor 1; LCR; locus control region; miR: microRNA.