Exploring epigenetic and microRNA approaches for γ-globin gene regulation.

Athena Starlard-Davenport, Ashley Fitzgerald, Betty S Pace

Experimental biology and medicine (Maywood, N.J.) 2021 Nov

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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.

Citation

Athena Starlard-Davenport, Ashley Fitzgerald, Betty S Pace. Exploring epigenetic and microRNA approaches for γ-globin gene regulation. Experimental biology and medicine (Maywood, N.J.). 2021 Nov;246(22):2347-2357